Imidazo[1,2-c]pyrimidine derivatives as prc2 inhibitors for treating cancer

ABSTRACT

Disclosed are compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, disclosed are compounds of Formula (I) and pharmaceutical compositions thereof, and methods of using the compounds and pharmaceutical compositions in, for example, methods of treating cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. Application No. 62/857,515, filed Jun. 5, 2019, the disclosure of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit the Polycomb Repressive Complex 2 (PRC2). In particular, the present invention relates to compounds, pharmaceutical compositions comprising the compounds and methods for use therefor.

BACKGROUND OF THE INVENTION

The Polycomb Repressive Complex 2 (PRC2) is a multiprotein complex that contributes to the epigenetic silencing of target genes to regulate development and homeostasis. The PRC2 complex comprises three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). Two additional non-essential subunits, AEBP2, and RbAp48, function to promote the enzymatic activity of the PRC2 complex (e.g., see Cao et al., (2002) Science 298: 1039-1043).

EZH2, the catalytic subunit of the PRC2 complex, is a histone methyltransferase that functions to silence target genes by tri-methylating lysine 27 of histone H3 (H3K27me3). EED is partially responsible for the recognition of trimethylated histone H3 lysine 27 and serves as scaffold protein for the assembly of the PRC2 complex. The interaction between EZH2 and EED subunits is essential for PRC2 complex histone methyltransferase activity and function (e.g., see Denisenko et al., (1998) Mol. Cell Biol. 18:5634-5642).

Aberrant PRC2 expression has been reported in several cancers. EZH2 is overexpressed in aggressive solid tumors, including prostate, breast, skin, bladder, liver, pancreas, and head and neck cancers. For instance, EZH2 transcript and protein were shown to be consistently elevated in invasive breast carcinoma compared with normal breast epithelia and were strongly associated with breast cancer aggressiveness. Overexpression of EZH2 in immortalized human mammary epithelial cell lines promotes anchorage-independent growth and cell invasion. EZH2-mediated cell invasion required an intact SET domain and histone deacetylase activity (Kleer et al., (2003) Proc. Natl Acad. Sci USA 100(20):11606-11611). There also is a greater risk of recurrence after prostatectomy in tumors expressing high levels of EZH2 (Varambally et al, (2008) Science 322:1695-1699).

In addition to overexpression, somatic activating and inactivating mutations of the EZH2 subunit have been reported. Somatic activating mutations in EZH2 have been identified in follicular lymphoma and diffuse large B-cell lymphomas that result in increased levels of H3K27me3 (for a review, see Helin and Dhanak (2013) Nature 502:480-488; Pasqualucci et al., (2011) Nature Genet. 43(9):830-837). These mutations taken together with overexpression of EZH2 in various solid tumors suggests that mis-regulation of EZH2 can lead to silencing of genes by the PRC2 complex that are important to tumor growth and survival. Interestingly, however, inhibitors of the PRC2 complex that target non-catalytic subunits, e.g., EED, retain potent activity against cell lines harboring EZH2 activating mutations (e.g., He et al., (2017) Nat Chem Biol.:13(8):922. doi: 10.1038/nchembio0817-922b).

SUMMARY OF THE INVENTION

PRC2 activity contributes to undesired cellular proliferation and invasiveness of tumor cells, in part, through trimethylation of H3K27. Since increased H3K27me3 levels contribute to cancer aggressiveness in many tumor types, the inhibition of PRC2 activity will provide therapeutic benefit for a wide range of cancers. The compounds of the present invention offer therapeutic benefit as inhibitors that bind to the EED subunit and are useful for negatively modulating the activity of PRC2 in a cell and for treating various forms of cancer.

There is a need to develop new PRC2 inhibitors that retain potency against EZH2-activating mutations and that demonstrate improved cellular potency, efficacy, stability and safety compared to inhibitors targeting the SET domain of EZH2. The compounds and compositions of the present invention advantageously overcome one or more of these shortcomings by providing potent, selective and orally active compounds that bind to EED and inhibit PRC2 activity irrespective of EZH2 mutation status or expression levels.

In one aspect of the invention, compounds are provided represented by Formula (I):

-   -   or a pharmaceutically acceptable salt thereof:

wherein:

represents a single or a double bond;

Z is O or S;

X is O, CR¹¹, CR¹¹OH, or C(R¹¹)₂, wherein:

when X is O,

is a single bond;

when X is C(R¹¹)₂,

is a single bond;

when X is CR¹¹OH,

is a single bond; or

when X is CR¹¹,

is a double bond;

R¹ is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the -L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R⁴;

R² is —C(R^(5a)R^(5b))R⁷ or heteroaryl;

each R³ is independently C1-C3 alkyl or halogen;

each R⁴ is independently cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, —Y²-haloalkyl; —Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, —Y¹-heterocyclyl, -L-N(R¹¹)₂, —Y¹—N(R¹¹)₂ or —Y²—N(R¹¹)₂ wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and —Y¹-heterocyclyl is optionally substituted with one or more R⁹;

L is a bond or C1-C4 alkylene;

Y¹ is a bond, —C(O)—, or —NHC(O)—;

Y² is a bond, —S—, —SO—, —SO₂—, or —NR⁵SO₂—;

R^(5a) and R^(5b) are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R^(5a) or R^(5b) is hydrogen;

R⁶ is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

R⁷ is —NR^(8a8b) wherein R^(8a) and R^(8b) together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from —O—, —N—, or —S— and optionally substituted with one or more R¹⁰; or

R⁷ is —OR^(8a) or —NHR^(8a) wherein R^(8a) is hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl;

each R⁹ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R¹¹)₂, C1-C6 alkyl or —Y¹-heterocyclyl, wherein the —Y¹-heterocyclyl is optionally substituted with one or more R¹⁰;

each R¹⁰ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

each R¹¹ is independently hydrogen or C1-C3 alkyl; and

n is 1 or 2.

In another aspect of the invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In yet another aspect of the invention, methods are provided for inhibiting PRC2 activity in a in a cell, comprising contacting the cell with a compound of Formula I. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with PRC2 mutation (e.g., a PRC2-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Also provided herein is a use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of PRC2.

Also provided herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a PRC2-associated disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to PRC2 inhibitors. In particular, the present invention relates to compounds that bind to EED to inhibit PRC2 activity, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor.

Definitions

Unless defined otherwise, all terms and ranges used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs, unless expressly defined otherwise. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with the present disclosure.

For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH₃—CH₂—), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

As used herein, “Polycomb Repressive Complex 2” or “PRC2 complex” refers to a mammalian multiprotein complex comprising three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12) and two additional non-essential subunits, AEBP2, and RbAp48.

As used herein, “EED” refers to the embryonic ectoderm development protein subunit of the PRC2 complex.

As used herein, “EZH2” or “EZH2 enzyme” refers to a mammalian histone methyltransferase, which is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), and functions to silence target genes by tri-methylating lysine 27 of histone H3 (H3K27me3).

As used herein, a “PRC2 inhibitor” refers to compounds of the present invention that are represented by formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of the PRC2 complex. While not wanting to be bound by any theory, we theorize that the inhibitors of the present invention may inhibit PRC2 enzymatic activity by binding to EED to prevent assembly of the PRC2 complex on histone H3 tails thereby inhibiting its activity.

A “PRC2-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having an activating EZH2 mutation and/or aberrant expression of PRC2. A non-limiting example of an PRC2-associated disease or disorder is a PRC2-associated cancer.

The term “amino” refers to —NH₂.

The term “acetyl” refers to “—C(O)CH₃.

As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

The term “alkyl” as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

The term “alkenyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

The term “alkoxy” refers to OC1-C6 alkyl.

The term “cycloalkyl” as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, “cycloalkyl” includes C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NR^(x), wherein R^(x) is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.

An “aryl” group is a C6-C14 aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes C₆, C₁₀, C₁₃, and C₁₄ cyclic hydrocarbon groups. An exemplary aryl group is a C₆-C₁₀ aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety. An exemplary aralkyl group is (C1-C6)alkyl(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.

A “heterocyclyl” or “heterocyclic” group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently —C(O)—, N, NR⁵, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.

As used herein, “-L-heterocyclyl” refers to a heterocyclyl group covalently linked to another group via an alkylene linker L, where L is C1-C4 alkylene.

As used herein, the term “heteroaryl” refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.

Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

A “-L-heteroaryl”, “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroalkyl groups comprise a C₁-C₆ alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.

An “arylene,” “heteroarylene,” or “heterocyclylene” group is an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.

The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.

The term “haloalkyl” refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chloromethyl, and fluoromethyl.

The term “hydroxyalkyl” refers to an alkyl chain, as defined herein, wherein at least on hydrogen of the alkyl chain has been replaced by hydroxyl.

As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of PRC2 complex.

As used herein, a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of PRC2 complex. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

As used herein, “treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.

As used herein, “amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition” refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

Compounds

In one aspect of the invention, compounds are provided represented by Formula (I):

or a pharmaceutically acceptable salt thereof:

wherein:

represents a single or a double bond;

Z is O or S;

X is O, CR¹¹, CR¹¹OH, or C(R¹¹)₂, wherein:

when X is O,

is a single bond;

when X is C(R¹¹)₂,

is a single bond;

when X is CR¹¹OH,

is a single bond; or

when X is CR¹¹,

is a double bond;

R¹ is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the -L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R⁴;

R² is —C(R^(5a)R^(5b))R⁷ or heteroaryl;

each R³ is independently C1-C3 alkyl or halogen;

each R⁴ is independently cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, —Y²-haloalkyl; —Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, —Y¹-heterocyclyl, -L-N(R¹¹)₂, —Y¹—N(R¹¹)₂ or —Y²—N(R¹¹)₂ wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and —Y¹-heterocyclyl is optionally substituted with one or more R⁹;

L is a bond or C1-C4 alkylene;

Y¹ is a bond, —C(O)—, or —NHC(O)—;

Y² is a bond, —S—, —SO—, —SO₂—, or —NR⁵SO₂—;

R^(5a) and R^(5b) are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R^(5a) or R^(5b) is hydrogen;

R⁶ is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

R⁷ is —NR^(8a8b) wherein R^(8a) and R^(8b) together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from —O—, —N—, or —S— and optionally substituted with one or more R¹⁰; or

R⁷ is —OR^(8a) or NHR^(8a) wherein R^(8a) is hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl;

each R⁹ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R¹¹)₂, C1-C6 alkyl or —Y¹-heterocyclyl, wherein the —Y¹-heterocyclyl is optionally substituted with one or more R¹⁰;

each R¹⁰ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

each R¹¹ is independently hydrogen or C1-C3 alkyl; and

n is 1 or 2.

In one embodiment, Z is O or S. In one embodiment, X is O, CR¹¹, CR¹¹OH or C(R¹¹)₂, wherein when X is O,

is a single bond; when X is C(R¹¹)₂,

is a single bond; when X is CR¹¹OH,

is a single bond; or when X is CR¹¹,

is a double bond. In one embodiment, n is one. In one embodiment, n is two.

In one embodiment, Z is O, X is O, n is one and

is a single bond. In another embodiment, Z is O, X is CR¹¹ and

is a double bond. In one embodiment, Z is O, X is C(R¹¹)₂, n is one, and

is a single bond. In one embodiment, Z is O, X is CR¹¹OH, n is one, and

is a single bond. In another embodiment, Z is O, X is C(R¹¹)₂, n is two, and

is a single bond. In yet another embodiment, Z is S, X is C(R¹¹)₂, n is one, and

is a single bond.

In one embodiment for compounds of Formula (I), R¹ is aryl, which is optionally substituted with one or more R⁴. In certain embodiments, the aryl is phenyl, which is optionally substituted with one or more R⁴.

In one embodiment for compounds of Formula (I), the aryl is substituted with a single R⁴ group. In one embodiment, the aryl is substituted with two R⁴ groups. In one embodiment, the aryl is substituted with three R⁴ groups. Exemplary aryl R⁴ groups include halogen, hydroxyl, haloalkyl, —Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, -L-N(R¹¹)₂, —Y¹—N(R¹¹)₂, —Y²N(R¹¹)₂, —Y²-haloalkyl, -L-heterocyclyl, or —Y¹-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl, or —Y¹-heterocyclyl is optionally substituted with one or more R⁹.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with —Y²—C1-C6 alkyl. In one embodiment, Y² is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl. In one embodiment, R¹ is phenyl substituted with the —Y²—C1-C6 alkyl, wherein Y² is —SO₂— and the C1-C6 alkyl is methyl. In one embodiment, R¹ is phenyl, which is disubstituted with methyl and —Y²—C1-C6 alkyl, wherein Y² is —SO²— and the C1-C6 alkyl is methyl.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted one R⁴, wherein R⁴ is a cyano group.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted one R⁴, wherein R⁴ is -L-heteroaryl. In certain embodiments, the -L-heteroaryl is tetrazolyl. In one embodiment, R¹ is phenyl substituted one R⁴, wherein R⁴ is —PO₃(C1-C3 alkyl)₂. In one embodiment, R¹ is phenyl substituted one R⁴, wherein R⁴ is —COOR¹¹. In one embodiment, R¹ is phenyl substituted one R⁴, wherein R⁴ is —O-L-N(R¹¹)₂. In one embodiment, R¹ is phenyl substituted one R⁴, wherein R⁴ is aralkyl.

nt for compounds of Formula (I), R¹ is phenyl substituted with at least one R⁴, wherein R⁴ is -L-N(R¹¹)₂. In one embodiment, L is a bond. In one embodiment, L is methylene. In one embodiment, each R¹¹ is independently hydrogen. In one embodiment, each R¹¹ is independently C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one R¹¹ is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl. In one embodiment, R¹ is phenyl substituted with -L-N(R¹¹)₂ and further substituted with one or more halogen and/or C1-C6 alkyl.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with one R⁴, wherein R⁴ is —Y¹—N(R¹¹)₂. In certain embodiments, Y¹ is —C(O)— and each R¹¹ is C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, Y¹ is —C(O)— and each R¹¹ is hydrogen. In one embodiment, Y¹ is —C(O)— and one R¹¹ is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl. In one embodiment, R¹ is phenyl substituted with —Y¹—N(R¹¹)₂ and further substituted with one or more halogen and/or C1-C6 alkyl.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with —Y²— haloalkyl, wherein Y² is —S— or —SO²— and the haloalkyl is trifluoromethyl.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with at least one -L-heterocyclyl or —Y¹-heterocyclyl, each heterocyclyl optionally substituted with one or more R⁹. In one embodiment, R¹ is phenyl substituted with one R⁴, wherein R⁴ is —Y¹— heterocyclyl optionally substituted with one or more R⁹. In one embodiment, Y¹ is —C(O)— and the heterocyclyl is piperazinyl optionally substituted with C1-C3 alkyl.

In certain embodiments for compounds of Formula (I), the R⁴ group is -L-heterocyclyl optionally substituted with one or more R⁹. In one embodiment, L is methylene and the heterocyclyl is pyrrolidinyl, piperdinyl, piperazinyl or 4-methyl-piperazinyl. In one embodiment, L is methylene and the heterocyclyl is azetindyl, pyrrolidinyl, piperdinyl, piperazinyl, piperazinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl or diazapanyl, each optionally substituted with one or more R⁹. Exemplary R⁹ groups include oxo, halogen, hydroxyalkyl and C1-C3 alkyl.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with —Y¹— heterocyclyl optionally substituted with one or more 9⁷. In certain embodiments, Y¹ is —C(O)— and the heterocyclyl is azetidinyl, pyrrolidinyl, piperdinyl, piperazinyl or 4-methyl-piperazinyl, each optionally further substituted with one or more halogen.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with -L-heteroaryl optionally substituted with one or more R⁹. In certain embodiments, the -L-heteroaryl is tetrazolyl.

In one embodiment for compounds of Formula (I), R¹ is phenyl substituted with —PO₃(C1-C3 alkyl)₂. In another embodiment, R¹ is phenyl substituted with —COOR¹¹. In one embodiment, R¹ is phenyl substituted with hydroxyalkyl, —O-L-N(R¹¹)₂ or aralkyl.

In one embodiment for compounds of Formula (I), R¹ is heteroaryl, which is optionally substituted with one or more R⁴. In certain embodiments, the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, or 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, each of which is optionally substituted with one or more R⁴.

In one embodiment for compounds of Formula (I), the heteroaryl is substituted with a single R⁴ group. In one embodiment, the heteroaryl is substituted with two R⁴ groups. In one embodiment, the heteroaryl is substituted with three R⁴ groups. Exemplary heteroaryl R⁴ groups include amino, cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, —Y²-haloalkyl-Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, —Y¹-heterocyclyl, -L-N(R¹¹)₂, or —Y¹—N(R¹¹)₂, wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and —Y¹-heterocyclyl is optionally substituted with one or more R⁹.

In one embodiment for compounds of Formula (I), R⁹ is amino, hydroxyl, cyano, alkoxy, or halogen. In one embodiment, R⁷ is C1-C3 alkyl. In one embodiment, R⁹ is halogen, wherein the halogen is fluorine or chlorine. In one embodiment, R⁹ is alkoxy, wherein the alkoxy is methoxy or ethoxy. In one embodiment, R⁹ is cycloalkyl, wherein the cycloalkyl is cyclopropyl.

In another embodiment for compounds of Formula (I), R¹ is heteroaryl and each R⁴ is independently hydroxyalkyl, heteroalkyl or haloalkyl. In certain embodiments, the hydroxyalkyl is hydroxymethyl, hydroxyethyl or 2-methyl, 2-hydroxypropyl. In certain embodiments, the heteroalkyl is methoxymethyl or methoxyethyl. In certain embodiments, the haloalkyl is fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl.

In certain embodiments for compounds of Formula (I), R¹ is heteroaryl and R⁴ is —Y¹—C1-C6 alkyl, wherein Y¹ is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl. In one embodiment, R⁴ is —Y¹—C1-C6 alkyl, wherein Y¹ is a —C(O)— and the C1-C6 alkyl is methyl, ethyl or isopropyl. In other embodiments, Y¹ is —NHC(O)— and the C1-C6 alkyl portion is methyl.

In one embodiment for compounds of Formula (I), R¹ is heteroaryl and R⁴ is —Y²—C1-C6 alkyl, wherein Y² is —SO₂— and the C1-C6 alkyl is methyl. In another embodiment, R⁴ is —Y²—C1-C6 alkyl, wherein Y² is —S— and the C1-C6 alkyl is methyl.

In one embodiment for compounds of Formula (I), R¹ is heteroaryl and R⁴ is —Y¹— heterocyclyl, which is optionally substituted with one or more R⁹. In one embodiment, Y¹ is a bond. In another embodiment, Y¹ is —C(O)—. In one embodiment, Y¹ is a bond and the heterocyclyl is azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl, piperazinyl or 4-methyl-piperazinyl. In one embodiment, R⁹ is C1-C3 alkyl. In one embodiment, R⁹ is halogen.

In one embodiment for compounds of Formula (I), the heteroaryl is substituted with at least one R⁴ that is -L-heterocyclyl, which is optionally substituted with one or more R⁹. In one embodiment, L is ethylene and the heterocyclyl is pyrrolidinyl, piperdinyl, piperazinyl or 4-methyl-piperazinyl. In one embodiment, L is methylene and the heterocyclyl is azetindyl, pyrrolidinyl, piperdinyl, piperazinyl, piperazinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl or diazapanyl, each optionally substituted with one or more R⁹.

In one embodiment, the R⁹ is independently -L-N(R¹¹)₂, hydroxyl, cyano, alkoxy, or halogen. In one embodiment, R⁹ is C1-C3 alkyl. In one embodiment, R⁷ is halogen, wherein the halogen is fluorine or chlorine. In one embodiment, R⁹ is alkoxy, wherein the alkoxy is methoxy or ethoxy. In one embodiment, R⁹ is cycloalkyl, wherein the cycloalkyl is cyclopropyl. In one embodiment, R⁹ is -L-N(R¹¹)₂. In one embodiment, L is a bond. In one embodiment, L is methylene. In one embodiment, each R¹¹ is independently hydrogen. In one embodiment, each is independently C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one R¹¹ is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl.

In one embodiment for compounds of Formula (I), R¹ is heteroaryl and R⁴ is -L-N(R¹¹)₂. In one embodiment, L is a bond. In one embodiment, L is methylene, ethylene or propylene. In one embodiment, each R¹¹ is independently C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl. In one embodiment, each R¹¹ is independently hydrogen.

In one embodiment for compounds of Formula (I), R¹ is heteroaryl and R⁴ is -L-heteroaryl, which is optionally substituted with one or more R⁹. In one embodiment, L is a bond. In one embodiment, L is C1-C3 alkylene. In one embodiment, the C1-C3 alkylene is methylene. In certain embodiments, the heteroaryl of the -L-heteroaryl is pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl or pyridazinyl. In one embodiment, the heteroaryl of the -L-heteroaryl is pyridyl.

In one embodiment for compounds of Formula (I), R¹ is heteroaryl which is substituted with two R⁴ groups independently selected from two —Y¹—C1-C6 alkyl groups; —Y¹—C1-C6 alkyl and alkoxy; —Y¹—C1-C6 alkyl and cycloalkyl; —Y¹—C1-C6 alkyl and haloalkyl; —Y¹—C1-C6 alkyl and amino; two alkoxy groups; alkoxy and halogen; alkoxy and cyano; and amino and haloalkyl. In certain embodiments, R⁴ is —Y¹—C1-C6 alkyl, wherein each Y¹ is a bond and each C1-C6 alkyl is methyl, ethyl or isopropyl. In one embodiment, the cycloalkyl is cyclopropyl. In one embodiment, the alkoxy is methoxy. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, the haloalkyl is trifluoromethyl or trifluoroethyl.

In one embodiment for compounds of Formula (I), R¹ is -L-heterocyclyl optionally substituted with one or more R⁴. In one embodiment, L is a bond and the heterocyclyl is tetrahydrofuranyl, piperdinyl, piperazinyl or morpholinyl. In one embodiment, L is a methylene and the heterocyclyl is azetidinyl, pyrrolidinyl or 3λ²-azabicyclo[3.1.0]hexanyl. In certain embodiments, the heterocyclyl is substituted with one or more R⁴ selected from oxo, halogen, alkoxy, hydroxyl and —Y¹—C1-C6 alkyl, wherein Y is a bond or —C(O)—.

In one embodiment for compounds of Formula (I), R² is —C(R^(5a)R^(5b))R⁷. In certain embodiments, R^(5a) is hydrogen and R^(5b) is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl. In other embodiments, R^(5a) is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl and R^(5b) is hydrogen.

In one embodiment for compounds of Formula (I), R⁷ is —OR^(8a). In one embodiment, R^(8a) is hydrogen or C1-C3 alkyl.

In one embodiment for compounds of Formula (I), R⁷ is —NR^(8a)R^(8b). In one embodiment, R^(8a) and R^(8b) are each hydrogen. In another embodiment, R^(8a) is hydrogen and R^(7b) is C1-C3 alkyl, halosulfonylalkyl, cycloalkyl or aralkyl.

In one embodiment for compounds of Formula (I), R⁷ is —NR^(8a)R^(8b), wherein R^(8a) and R^(8b) together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from —O—, —N—, or —S— and optionally substituted with one or more R¹⁰. In certain embodiments, the 4-8 membered saturated or partially saturated heterocyclyl is azetidinyl or 3-hydroxy-azetidinyl.

In one embodiment for compounds of Formula (I), R² is heteroaryl. In certain embodiments, the heteroaryl is tetrazolyl, oxazolyl or oxidiazolyl.

In one embodiment, n is zero. In one embodiment, n is one and R³ is halogen. In certain embodiments, the halogen is fluorine or chlorine. In one embodiment, the halogen is fluorine.

In one embodiment, R⁶ is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl. In certain embodiments, R⁶ is hydrogen. In other embodiments, R⁶ is methyl, ethyl or propyl.

In one embodiment, the cyclyl portion of R⁴ group is substituted with one R⁹ group. In certain embodiments, R⁹ is oxo, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R¹¹)₂ or C1-C3 alkyl. In certain embodiments, R⁹ is C1-C3 alkyl, wherein the C1-C3 alkyl is methyl, ethyl or isopropyl. In certain embodiments, R⁹ is halogen, wherein the halogen is fluorine or chlorine. In certain embodiments, R⁹ is oxo.

In one embodiment, the cyclyl portion of R⁴ group is substituted with two R⁹ groups. In certain embodiments, the two R⁹ groups are each halogen, wherein each halogen is fluorine.

In one embodiment, the compound is:

Pharmaceutical Compositions

In another aspect, the invention provides pharmaceutical compositions comprising a PRC2 inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.

The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula —NR+Z—, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

The pharmaceutical compositions comprising compounds of the present invention may be used in the methods described herein.

Methods of Use

In yet another aspect, the invention provides for methods for inhibiting PRC2 activity in a cell, comprising contacting the cell in which inhibition of PRC2 activity is desired with a therapeutically effective amount of a compound of formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.

The compositions and methods provided herein are particularly deemed useful for inhibiting PRC2 activity in a cell. In one embodiment, a cell in which inhibition of PRC2 activity is desired is contacted with a therapeutically effective amount of a compound of formula (I) to negatively modulate the activity of PRC2. In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of formula (I) may be used.

By negatively modulating the activity of PRC2, particularly in cases for cells overexpressing the EZH2 enzyme or somatic mutations that activate the EZH2 enzyme, the methods are designed to restore normal cellular transcription expression patterns, e.g., by altering methylation pattern of H3K27, to inhibition undesired cellular proliferation resulting from enhanced PRC2 activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to affect the desired negative modulation of PRC2. The degree of mono- and dimethylation of histone H3K27 may be monitored in the cell using well known methods, including those described in Example A below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.

In another aspect, methods of treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.

The compositions and methods provided herein may be used for the treatment of a wide variety of cancer including tumors such as prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. The degree of mono- and dimethylation of histone H3K27 may be monitored in the patient using well known methods, including those described in Example A below, to access the effectiveness of treatment, along with other prognostic or biological factors, and dosages may be adjusted accordingly by the attending medical practitioner.

General Reaction Scheme, Intermediates and Examples General Reaction Schemes

The compounds of the present invention may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art.

For instance, intermediates for compounds and compounds of formula (I) of the present invention may be prepared according to General Reaction Schemes I-IV:

In General Reaction Scheme I, R²-ester substituted imidazo[1,2-c]pyrimidine A is coupled to R³ optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate C. A boronic acid derivative (Y)—R¹ D is coupled via a Suzuki reaction with halogen substituted Intermediate C in the presence of a suitable base, e.g., sodium carbonate, and the R² ester is converted to the alcohol via a reducing agent such as lithium aluminum hydride to generate intermediate alcohol E. The alcohol E is converted to the corresponding aldehyde F via oxidation using a suitable oxidant, e.g., Dess-Martin periodinane, which is then converted to the secondary alcohol by treatment with an organometallic reagent such as a Grignard reagent to form title compound alcohol G.

In General Reaction Scheme II, R²-cyano substituted imidazo[1,2-c]pyrimidine H is coupled to R³ optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate I. A boronic acid derivative (Y)—R¹ D is coupled via a Suzuki reaction with halogen substituted Intermediate I in the presence of a suitable base, e.g., sodium carbonate, and the R² cyano is converted to the amine via a metal-mediated hydrogenation using hydrogen gas and a suitable metal such as Raney nickel to form title compound amine J.

In General Reaction Scheme III, Intermediate F can undergo a reductive amination reaction with an R^(8a8b) optionally substituted Intermediate amine K using an appropriate reducing agent such as sodium triacetoxyborohydride, to form the title compound L.

In General Reaction Scheme IV, an organometallic reagent, such as an alkyl magnesium halide undergoes nucleophilic addition to R²-cyano imidazo[1,2-c]pyrimidine I to give the R¹¹ substituted amine intermediate M. The resultant amine M is protected with an appropriate protecting group, e.g. tert-butyloxycarbonyl to give Intermediate N. The Intermediate N can then be coupled with a boronic acid derivative (Y)—R¹ D via a Suzuki reaction in the presence of a suitable base, such as sodium carbonate, and the protecting group removed from the resultant product via treatment with a strong acid, e.g. TFA to give the desired title compound O.

The following Intermediates are intended to illustrate various intermediates that may be used to prepare compounds of the present invention and are not intended to limit the scope of the invention.

An exemplary Intermediate A, Intermediate A-1, may be used to synthesize compounds of formula (I). A mixture of 6-amino-5-bromo-1H-pyrimidin-2-one (2.00 g, 10.5 mmol, 1.00 equiv) and ethyl 3-bromo-2-oxo-propanoate (3.12 g, 16.0 mmol, 2.00 mL, 1.52 equiv) in DMF (20.0 mL) was stirred at 80° C. for 3 h. The mixture was concentrated in vacuo to give a residue. To the residue was added water (50.0 mL), the mixture was extracted with ethyl acetate (80.0 mL×3) and the organic layer was concentrated in vacuo. The crude material was heated in methanol (5.00 mL) and the solid was removed by filtration The filtrate was concentrated under reduced pressure to provide ethyl 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxylate (1.00 g, 3.50 mmol, 33.2% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=12.09 (br s, 1H), 8.32 (s, 1H), 7.73 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).

A mixture of ethyl 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxylate (500 mg, 1.75 mmol, 1 equiv) and DIEA (564 mg, 4.37 mmol, 760 uL, 2.50 equiv) in POCl₃ (8.00 mL) was stirred for 15 h at 120° C. The mixture was concentrated in vacuo to afford the crude residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 10/1 to 1/1) to provide ethyl 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carboxylate (380 mg, 1.25 mmol, 71.4% yield) as a yellow solid.

¹H NMR (400 MHz, CD₃OD) δ=8.61 (s, 1H), 8.20 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

A second exemplary Intermediate A, Intermediate A-2, also may be used to synthesize compounds of formula (I). To a solution of ethyl 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxylate (3.00 g, 10.2 mmol, 1.00 equiv) in MeOH (60.0 mL) was added NaOH (1 M, 30.5 mL, 3.00 equiv). The resultant mixture was stirred at 60° C. for 1 h. Subsequently, the reaction mixture was concentrated and the pH was adjusted to 4 with 1M aq HCl at which time a precipitate formed. The solid was filtered and dried under vacuum to provide 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxylic acid (2.60 g, 10.1 mmol, 99.1% yield) as a brown solid.

To a solution of 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxylic acid (2.60 g, 10.1 mmol, 1.00 equiv) in DMF (60.0 mL) was added NH₄Cl (1.62 g, 30.2 mmol, 3.00 equiv), DIPEA (11.7 g, 90.7 mmol, 15.8 mL, 9.00 equiv) and HATU (5.75 g, 15.1 mmol, 1.50 equiv). The mixture was stirred at 15° C. for 12 h and was subsequently concentrated in vacuo. The resultant residue was triturated with MeOH (30 mL). The precipitate was washed with water 50 mL, filtered and the filtrate was concentrated in vacuo to afford 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxamide (1.78 g, 6.92 mmol, 68.7% yield) as a light-yellow solid. LC-MS [M+1]: 257.0.

To a solution of 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxamide (1.70 g, 6.61 mmol, 1.00 equiv) in POCl₃ (20.0 mL) was added DIPEA (4.27 g, 33.1 mmol, 5.76 mL, 5.00 equiv) dropwise at 0° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was filtered and concentrated at reduced pressure to provide the crude material. The crude residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 4/1) to afford 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carbonitrile (950 mg, 3.69 mmol, 55.8% yield) as a light-yellow solid. LC-MS [M+1]: 258.9.

Alternatively, Intermediate A-2 may be prepared on a large scale as follows:

To a solution of cytosine (300 g, 2.70 mol, 1.00 equiv) in DMF (1.5 L) was added NBS (480 g, 2.70 mol, 1.00 equiv). The mixture was stirred at 25° C. for 10 h at which time the crude ¹H NMR spectrum indicated that the reaction was complete. The reaction mixture was filtered and the filter cake was washed with water (1 L×4). The solid was collected and dried under reduced pressure to afford 5-bromocytosine (480 g, 2.53 mol, 93.6% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (br s, 1H), 11.36-10.16 (m, 1H), 7.74 (s, 1H), 6.83 (br s, 2H).

A mixture of compound 5-bromocytosine (150 g, 789 mmol, 1.00 equiv) and ethyl 3-bromo-2-oxo-propanoate (385 g, 1.97 mol, 247 mL, 2.50 equiv) in AcOH (1.5 L) was stirred at 120° C. for 2 h. The crude ¹H NMR spectrum indicated that the reaction was complete. Three batches were concentrated to provide a residue that was triturated with MTBE (3 L) and filtered. The filter cake was washed with water (1 L×4) and dried to afford ethyl 8-bromo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate (300 g, 1.05 mol, 44.3% yield) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.47-11.64 (m, 1H), 8.33 (s, 1H), 8.06 (s, 2H), 7.73 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

To a solution of ethyl 8-bromo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate (150 g, 524 mmol, 1.00 equiv) in MeOH (1.5 L) was added NaOH (2 M, 786 mL, 3.00 equiv). The mixture was stirred at 65° C. for 2 h at which time the LCMS indicated that the reaction was complete. The reaction mixture was concentrated to give a residue that was acidified with HCl (2 M) to pH=2-3. The solid was filtered and the filter cake was washed with water (800 mL×4). The solid was collected and dried under vacuum to afford 8-bromo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (140 g, 543 mmol, 51.7% yield) as a brown solid. LCMS (M+1): 257.9.

¹H NMR (400 MHz, DMSO-d₆) δ 12.86-11.28 (m, 1H), 8.27 (s, 1H), 7.73 (s, 1H).

To a suspension of 8-bromo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (120 g, 465 mmol, 1.00 equiv) in SOCl₂ (787 g, 6.62 mol, 480 mL, 14.2 equiv) was added DMF (340 mg, 4.65 mmol, 358 μL, 0.01 equiv) and the mixture was stirred at 80° C. for 2 h. The solution was concentrated to give a residue that was dissolved in DCM (200 mL). The resulting mixture was added dropwise to conc. ammonium hydroxide (1.09 kg, 9.35 mol, 1.20 L, 20.1 equiv) at 0° C. and the mixture was subsequently stirred at 25° C. for 1 h. LCMS indicated that the reaction was complete. The mixture was filtered, the filter cake was washed with MeOH (200 mL), and the solid was dried under vacuum to afford 8-bromo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (120 g, crude) as a brown solid. LCMS (M+1): 257.0/259.0.

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.66 (s, 1H), 7.56 (br s, 1H), 7.41 (br s, 1H).

To a solution of 8-bromo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (20.0 g, 77.8 mmol, 1.00 equiv) in POCl₃ (388 g, 2.53 mol, 235 mL, 32.5 equiv) was added DIEA (50.3 g, 389 mmol, 67.8 mL, 5.00 equiv) dropwise at 0° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture (4 identical batches combined) was cooled to room temperature and was concentrated to afford a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 5:1) to provide 8-bromo-5-chloroimidazo[1,2-c]pyrimidine-2-carbonitrile (19.9 g, 76.1 mmol, 24.5% yield, 98.6% purity) as an off-white solid. LCMS (M+1): 388.0/390.0.

¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.36 (s, 1H).

An exemplary Intermediate B, Intermediate B-1, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂, and

is a single bond. A mixture of 3-bromophenol (10.0 g, 57.8 mmol, 1.00 equiv) and 2-bromo-1,1-diethoxy-ethane (13.7 g, 69.4 mmol, 10.4 mL, 1.20 equiv) in DMF (100 mL) was added potassium carbonate (24.0 g, 173 mmol, 3.00 equiv). The resultant mixture was stirred at 110° C. for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with petroleum ether (100 mL) and washed with brine (50.0 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether) to afford 1-bromo-3-(2,2-diethoxyethoxy)benzene (17.0 g, 48.2 mmol, 83.4% yield, 82.0% purity) as a light yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.17-7.07 (m, 3H), 6.88-6.84 (m, 1H), 4.82 (t, J=5.2 Hz, 1H), 3.99 (d, J=5.2 Hz, 2H), 3.80-3.74 (m, 1H), 3.80-3.73 (m, 2H), 3.68-3.61 (m, 2H), 1.25 (t, J=7.2 Hz, 6H).

To a solution of polyphosphoric acid (21.5 g, 63.6 mmol, 1.50 equiv) in toluene (80.0 mL) was added 1-bromo-3-(2,2-diethoxyethoxy)benzene (15.0 g, 42.5 mmol, 1.00 equiv) at 90° C. The mixture was stirred at 90° C. for 2 h and then concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether) to afford 4-bromobenzofuran (5.20 g, 13.2 mmol, 31.0% yield, 50.0% purity) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.70 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.37 (dd, J=1.6, 8.4 Hz, 1H), 7.21-7.15 (m, 1H), 6.85-6.80 (m, 1H), 6.78-6.73 (m, 1H).

To a solution of 4-bromobenzofuran (5.20 g, 13.2 mmol, 1.00 equiv) in DMAC (50.0 mL) was added zinc cyanide (6.85 g, 58.3 mmol, 4.42 equiv) and Pd(PPh₃)₄ (1.52 g, 1.32 mmol, 0.100 equiv). The mixture was stirred at 140° C. for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (80.0 mL), washed with brine (50.0 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate=50/1 to 0/1) to afford benzofuran-4-carbonitrile (1.60 g, 10.1 mmol, 76.2% yield, 90.0% purity) as a light-yellow oil.

1H NMR (400 MHz, CDCl₃) δ=7.80 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 7.03-7.00 (m, 1H).

To a solution of benzofuran-4-carbonitrile (750 mg, 4.72 mmol, 1.00 equiv) in methyl alcohol (10.0 mL) was added Boc₂O (3.09 g, 14.2 mmol, 3.00 equiv) and Pd/C (4.72 mmol, 10.0 w. %, 1.00 equiv). The mixture was stirred at 30° C. for 24 h under hydrogen (50.0 psi). The reaction mixture was filtered and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 50/1) to afford tert-butyl N-(2,3-dihydrobenzofuran-4-ylmethyl) carbamate (140 mg, 562 μmol, 11.9% yield) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.10 (t, J=8.0 Hz, 1H), 6.74 (dd, J=8.0, 14.0 Hz, 2H), 4.75 (br s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.28 (br d, J=5.6 Hz, 2H), 3.20 (t, J=8.8 Hz, 2H), 1.47 (s, 9H).

To a solution of tert-butyl N-(2,3-dihydrobenzofuran-4-ylmethyl) carbamate (140 mg, 562 μmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (640 mg, 5.62 mmol, 416 μL, 10.0 equiv). The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with DCM (10.0 mL) and was added to a saturated potassium carbonate aqueous solution (10.0 mL). The biphasic mixture was stirred at 25° C. for 0.5 h. The organic phase was separated, dried over sodium sulfate, concentrated in vacuo to afford 2,3-dihydrobenzofuran-4-ylmethanamine (80.0 mg, 483 μmol, 85.9% yield, 90.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl₃) δ=7.13 (t, J=8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 4.60 (t, J=8.8 Hz, 2H), 3.82 (s, 2H), 3.20 (t, J=8.8 Hz, 2H).

A second exemplary Intermediate B, Intermediate B-2, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR¹¹,

is a double bond and one R³ is fluorine. To a mixture of 5-fluorobenzofuran-4-carbonitrile (250 mg, 1.47 mmol, 1.00 equiv) and Raney-Ni (126 mg, 1.47 mmol, 1.00 equiv) in methyl alcohol (6.60 mL) was added ammonium hydroxide (1.60 mL). The mixture was purged with nitrogen and stirred at 25° C. for 12 h under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford (5-fluorobenzofuran-4-yl) methanamine (220 mg, 1.20 mmol, 81.3% yield, 90.0% purity) as a brown oil.

¹H NMR (400 MHz, CDCl₃) δ=7.67 (s, 1H), 7.33 (br d, J=5.6 Hz, 1H), 7.04 (br t, J=9.6 Hz, 1H), 6.90 (s, 1H), 4.54-3.78 (m, 2H).

A third exemplary Intermediate B, Intermediate B-3, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is chlorine. To a solution of benzofuran-4-carboxylic acid (900 mg, 5.55 mmol, 1 equiv) in MeOH (9.00 mL) was added palladium on activated carbon (20.0 mg, 555 μmol, 10.0 wt %, 0.10 equiv) under nitrogen. The vessel was evacuated and purged with hydrogen several times. The mixture was stirred at 25° C. for 12 h under hydrogen (50.0 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 2,3-dihydrobenzofuran-4-carboxylic acid (750 mg, 3.66 mmol, 65.9% yield, 80.0% purity) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.38 (d, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.54 (t, J=8.8 Hz, 2H), 3.45 (br t, J=8.8 Hz, 2H).

To a solution of 2,3-dihydrobenzofuran-4-carboxylic acid (750 mg, 3.66 mmol, 1.00 equiv) in DMF (1.00 mL) was added Pd(OAc)₂ (82.1 mg, 366 μmol, 0.10 equiv) and NCS (586 mg, 4.39 mmol, 1.20 equiv). The reaction was stirred at 110° C. for 12 h under an atmosphere of nitrogen. The reaction mixture was filtered and concentrated in vacuo and the resultant residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1 to dichloromethane/methanol=10/1) to afford 5-chloro-2,3-dihydrobenzofuran-4-carboxylic acid (600 mg, crude) as a yellow oil. LC-MS: [M+1] 198.9.

To a solution of 5-chloro-2,3-dihydrobenzofuran-4-carboxylic acid (600 mg, 3.02 mmol, 1.00 equiv) in DMF (5.00 mL) was added ammonium chloride (242 mg, 4.53 mmol, 1.50 equiv), HATU (2.30 g, 6.04 mmol, 2.00 equiv), DIEA (1.17 g, 9.06 mmol, 1.58 mL, 3.00 equiv). The reaction mixture was stirred at 25° C. for 12 h and concentrated in vacuo to give the crude material, which was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to afford 5-chloro-2,3-dihydrobenzofuran-4-carboxamide (700 mg, 2.83 mmol, 93.8% yield, 80.0% purity) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.87 (br s, 1H), 7.63 (br s, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.58 (t, J=8.8 Hz, 2H), 3.18 (t, J=8.8 Hz, 2H).

To a solution of 5-chloro-2,3-dihydrobenzofuran-4-carboxamide (300 mg, 1.21 mmol, 1.00 equiv) in THF (5.00 mL) was added dropwise BH₃-DMS (10.0 M, 607 μL, 5.00 equiv). The reaction was stirred at 70° C. for 2.5 h, quenched with MeOH (5.00 mL) and concentrated in vacuo to provide a residue. To the residue was added water (20.0 mL) and the mixture was extracted with DCM (20.0 mL×3). The combined organic phase was washed with brine (20.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to afford (5-chloro-2,3-dihydrobenzofuran-4-yl)methanamine (240 mg, crude) as a brown oil. LC-MS: [M-16] 167.1.

A fourth exemplary Intermediate B, Intermediate B-4, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine. To a solution of 3-bromo-4-fluoro-phenol (100 g, 524 mmol, 1.00 equiv) and 2-bromo-1,1-diethoxy-ethane (124 g, 628 mmol, 94.5 mL, 1.20 equiv) in DMF (600 mL) was added potassium carbonate (217 g, 1.57 mol, 3.00 equiv). The mixture was stirred at 110° C. for 12 h under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (500 mL), washed with brine (500 ml×5) and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 20/1) to afford 2-bromo-4-(2,2-diethoxyethoxy)-1-fluoro-benzene (171 g, 501 mmol, 95.7% yield, 90.0% purity) as a light-yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.12 (dd, J=2.8, 5.6 Hz, 1H), 7.06-6.98 (m, 1H), 6.84 (td, J=3.2, 9.2 Hz, 1H), 4.81 (t, J=5.2 Hz, 1H), 3.96 (d, J=5.2 Hz, 2H), 3.81-3.72 (m, 2H), 3.68-3.59 (m, 2H), 1.25 (t, J=7.2 Hz, 6H).

To a solution of PPA (254 g, 752 mmol, 1.50 equiv) in toluene (1.30 L) was added 2-bromo-4-(2,2-diethoxyethoxy)-1-fluoro-benzene (171 g, 501 mmol, 1.00 equiv) at 90° C. The mixture was stirred at 95° C. for 2 h and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether) to give 4-bromo-5-fluoro-benzofuran (87.3 g, 203 mmol, 40.5% yield, 50.0% purity) as a yellow oil. To a mixture of 4-bromo-5-fluoro-benzofuran (85.5 g, 398 mmol, 1.00 equiv) and 6-bromo-5-fluoro-benzofuran (85.5 g, 398 mmol, 1.00 equiv) in DMAC (1.50 L) was added zinc cyanide (31.1 g, 264 mmol, 0.67 equiv) and Pd(PPh₃)₄ (23.0 g, 19.9 mmol, 0.05 equiv). The mixture was stirred at 90° C. for 12 h under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (1.00 L) and filtered. The filtrate was washed with brine (1.00 L X 3) and the organic layer was concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 50/1) to afford 4-bromo-5-fluoro-benzofuran (78 g, crude) as a white solid.

To a solution of 4-bromo-5-fluoro-benzofuran (87.3 g, 203 mmol, 1.00 equiv) in DMAC (600 mL) was added zinc cyanide (94.6 g, 805 mmol, 3.97 equiv) and Pd(PPh₃)₄ (23.5 g, 20.3 mmol, 0.10 equiv). The mixture was stirred at 110° C. for 12 h under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (500 mL), washed with brine (400 mL×5), dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 50/1) to afford 5-fluorobenzofuran-4-carbonitrile (20.0 g, 118 mmol, 58.1% yield, 95.0% purity) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=7.84 (d, J=2.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.14 (t, J=9.2 Hz, 1H), 7.02-6.96 (m, 1H).

To a solution of 5-fluorobenzofuran-4-carbonitrile (19.6 g, 116 mmol, 1.00 equiv) in methyl alcohol (1.00 L) was added di-tert-butyl dicarbonate (75.7 g, 347 mmol, 3.00 equiv) and Pd/C 10 w. % (1.16 g). The mixture was stirred at 35° C. for 24 h under an atmosphere of hydrogen gas (50.0 psi). The reaction mixture was filtered and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 3/1) to afford tert-butyl N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]carbamate (22.0 g, 78.2 mmol, 67.7% yield, 95.0% purity) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=6.82-6.76 (m, 1H), 6.62 (dd, J=4.0, 8.8 Hz, 1H), 4.88 (br s, 1H), 4.60 (t, J=8.8 Hz, 2H), 4.30 (br d, J=6.0 Hz, 2H), 3.30 (br t, J=8.8 Hz, 2H), 1.44 (s, 9H).

To a solution of tert-butyl N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl] carbamate (22.0 g, 78.2 mmol, 1.00 equiv) in DCM (200 mL) was added TFA (89.2 g, 782 mmol, 57.9 mL, 10.0 equiv). The mixture was stirred at 25° C. for 0.5 h and subsequently quenched with satd aq potassium carbonate (200 mL). The mixture was allowed to stir at 25° C. for 0.5 hour. The organic phase was separated and dried over sodium sulfate, concentrated in vacuo to afford (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (13.0 g, 73.9 mmol, 94.5% yield, 95.0% purity) as a light yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=6.85-6.76 (m, 1H), 6.60 (dd, J=4.0, 8.8 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 3.82 (s, 2H), 3.24 (t, J=8.8 Hz, 2H).

Alternatively, Intermediate B-4 may be prepared on a large scale as follows:

To a solution of 3-bromo-4-fluorophenol (1.00 kg, 5.24 mol, 1.00 equiv) and Cs₂CO₃ (3.41 kg, 10.5 mol, 2.00 equiv) in DMF (5.00 L) was added compound 2-bromo-1,1-diethoxyethane (1.24 kg, 6.28 mol, 1.20 equiv) in one portion. The suspension was stirred at 110° C. for 12 h. TLC (petroleum ether/ethyl acetate=10/1, R_(f)=0.50) indicated that the reaction was complete. The reaction mixture was filtered, diluted with water (15.0 L) and extracted with MTBE (5.00 L x 2). The combined organic layers were washed with brine (3.00 L), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give compound 2-bromo-4-(2,2-diethoxyethoxy)-1-fluorobenzene (1.61 kg, crude) as a yellow oil.

Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of polyphosphoric acid (1.30 kg) in toluene (2.40 L) was added 2-bromo-4-(2,2-diethoxyethoxy)-1-fluorobenzene (800 g, 2.60 mol, 1.00 equiv) in one portion at 90° C. The mixture was stirred at 90° C. for 3 h. TLC (petroleum ether/EtOAc=10/1, R_(f)=0.6) indicated that the reaction was complete. The two reactions were combined prior to work up. The mixture was poured into water (6.00 L) and extracted with MTBE (6.00 L x 2). The combined organic layer was washed with brine (5.00 L x 2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/0 to 100/1) to give a -1:1 mixture of 4-bromo-5-fluorobenzofuran and 6-bromo-5-fluorobenzofuran (800 g, 3.72 mol, 71.4% yield) as a brown oil.

Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of 4-bromo-5-fluorobenzofuran (150 g, 698 mmol, 1.00 equiv) and 6-bromo-5-fluorobenzofuran (150 g, 698 mmol, 1.00 equiv) in DMA (2.40 L) was added Zn(CN)₂ (49.2 g, 419 mmol, 0.60 equiv) and Pd(PPh₃)₄ (40.3 g, 34.9 mmol, 0.05 equiv) in one portion at 25° C. under N₂. The mixture was stirred at 90° C. for 12 h. TLC (petroleum ether/EtOAc=10/1) indicated the consumption of the undesired isomer (6-bromo-5-fluorobenzofuran). The two reactions were combined prior to work up. The mixture was diluted with EtOAc (5.00 L) and filtered. The filtrate was poured into water (8.00 L) and the mixture was extracted with EtOAc (3.00 L x 2). The combined organic phase was washed with brine (4.00 L x 2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/0 to 5/1) to give compound 4-bromo-5-fluorobenzofuran (340 g) as a yellow oil.

Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of compound 4-bromo-5-fluorobenzofuran (170 g, 791 mmol, 1.00 equiv) in DMA (1.30 L) was added Zn(CN)₂ (92.8 g, 791 mmol, 1.00 eq.) and Pd(PPh₃)₄ (91.4 g, 79.1 mmol, 0.10 equiv) in one portion at 25° C. under N₂. The resultant mixture was stirred at 120° C. for 12 h. TLC (petroleum ether/EtOAc=10/1) indicated that the reaction was complete. The two reactions were combined prior to work up and the mixture was poured into water (3.00 L) and EtOAc (4.00 L), filtered, and the filtrate was extracted with EtOAc (2.00 L x 2). The combined organic layer was washed with brine (3.00 L×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/0 to 50/1) to afford compound 5-fluorobenzofuran-4-carbonitrile (120 g, 745 mmol, 47.1% yield) as a yellow oil.

¹H NMR (400 MHz, CD₃OD) δ 8.06 (d, J=2.0 Hz, 1H), 7.82-7.86 (m, 1H), 7.23-7.28 (m, 1H), 7.02 (d, J=2.0 Hz, 1H).

Two reactions were conducted in parallel on the same scale and combined during the workup. To a solution of compound 5-fluorobenzofuran-4-carbonitrile (60.0 g, 372 mmol, 1.00 equiv) in MeOH (1.50 L) was added Boc₂O (122 g, 559 mmol, 1.50 equiv) and Pd/C (12.0 g, 10 wt %) under N₂. The suspension was evacuated and purged with Hz several times and the mixture was stirred under H₂ (50 psi) at 50° C. for 12 h. TLC (petroleum ether/EtOAc=10/1) indicated that the reaction was complete. The two reactions were combined prior to work up and filtered. The filtrate was concentrated to afford a residue that was triturated with petroleum ether (500 mL), filtered, and dried at 45° C. under vacuum to provide tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (100 g, 374 mmol, 50.2% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 6.76-6.81 (m, 1H), 6.60-6.63 (m, 1H), 4.60 (t, J=8.8 Hz, 2H), 4.29-4.31 (m, 2H), 3.30 (t, J=8.8 Hz, 2H), 1.44 (s, 9H).

Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (50.0 g, 187 mmol, 1.00 equiv) in EtOAc (400 mL) was added HCl/EtOAc (300 mL, 4M) in one portion at 25° C. under N₂. The resultant mixture was stirred for 4 h at which time TLC (petroleum ether/EtOAc=5/1) indicated that the reaction was complete. The two reactions were combined prior to work up, filtered, and the filter cake was washed by MTBE (100 mL×2). The filter cake was dissolved in water (200 mL) and the pH was adjusted to 9 with sat. aq. K₂CO₃ at 0° C. prior to extraction with DCM (200 mL×4). The combined organic phase was washed with brine (200 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (50.0 g, 299 mmol, 79.9% yield) as a brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (br. s., 3H), 6.97 (m, 1H), 6.77-6.80 (m, 1H), 4.55-4.59 (m, 2H), 3.94 (s, 2H), 3.37-3.42 (m, 2H).

A fifth exemplary Intermediate B, Intermediate B-5, may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine. A mixture of 3-bromo-4-fluoro-benzenethiol (4.50 g, 21.7 mmol, 1.00 equiv), 2-bromo-1,1-diethoxy-ethane (4.71 g, 23.9 mmol, 3.60 mL, 1.10 equiv), and potassium carbonate (3.60 g, 26.1 mmol, 1.20 equiv) in DMF (50.0 mL) was purged with nitrogen. The mixture was stirred at 80° C. for 0.5 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to provide a residue, which was purified by column chromatography (petroleum ether/ethyl acetate, 20/1 to 5/1) to afford 2-bromo-4-(2,2-diethoxyethylsulfanyl)-1-fluoro-benzene (6.2 g, 19.2 mmol, 88.3% yield) as a colorless liquid.

¹H NMR (400 MHz, CDCl₃) δ=7.63 (dd, J=2.4, 6.4 Hz, 1H), 7.32 (ddd, J=2.4, 4.4, 8.8 Hz, 1H), 7.03 (t, J=8.4 Hz, 1H), 4.63 (t, J=5.6 Hz, 1H), 3.72-3.65 (m, 2H), 3.57-3.51 (m, 2H), 3.08 (d, J=5.6 Hz, 2H), 1.20 (t, J=7.2 Hz, 6H).

To a solution of polyphosphoric acid (39 g, 710 μL, 1.00 equiv) in chlorobenzene (70.0 mL) was added 2-bromo-4-(2,2-diethoxyethylsulfanyl)-1-fluoro-benzene (5.9 g, 18.3 mmol, 1.00 equiv) and the resultant mixture was stirred at 130° C. for 12 h. The mixture was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (petroleum ether) to afford 4-bromo-5-fluoro-benzothiophene (2.50 g, 10.8 mmol, 29.8% yield, 50% purity) as a colorless liquid.

¹H NMR (400 MHz, CDCl₃) δ=7.75 (dd, J=4.4, 8.8 Hz, 1H), 7.61 (d, J=5.6 Hz, 1H), 7.49 (d, J=5.6 Hz, 1H), 7.17 (t, J=8.8 Hz, 1H).

To a solution of 4-bromo-5-fluoro-benzothiophene (1.25 g, 5.41 mmol, 1.00 equiv) in DMAC (12.0 mL) was added zinc cyanide (953 mg, 8.11 mmol, 515 μL, 1.50 equiv) and Pd(PPh₃)₄ (938 mg, 811 μmol, 0.150 equiv). The mixture was stirred at 100° C. for 12 h under an atmosphere of nitrogen. Water (50.0 mL) was added and the mixture was extracted with ethyl acetate (80.0 mL×3). The combined organic layer was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (petroleum ether) to afford 5-fluorobenzothiophene-4-carbonitrile (530 mg, 2.99 mmol, 27.7% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=8.05 (dd, J=4.4, 8.8 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.57 (d, J=5.6 Hz, 1H), 7.23 (t, J=8.8 Hz, 1H).

To a mixture of 5-fluorobenzothiophene-4-carbonitrile (300 mg, 1.69 mmol, 1.00 equiv) in THF (2.00 mL) was added BH₃-Me₂S (10 M, 677 μL, 4.00 equiv) at 0° C. and the mixture was stirred for 6 h at 75° C. The mixture was cooled to room temperature and was quenched with ethanol (10.0 mL) and the pH was adjusted to 3 with aq HCl (2 M). The mixture was concentrated in vacuo to provide a residue to which water (20.0 mL) was added. The aqueous mixture was extracted with ethyl acetate (40.0 mL×4) and the combined organic layer was concentrated to afford (5-fluorobenzothiophen-4-yl)methanamine (150 mg, 828 μmol, 48.9% yield) as a yellow solid.

A sixth exemplary Intermediate B, Intermediate B-6, may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine.

To a solution of 2-bromo-6-hydroxy-benzaldehyde (0.30 g, 1.49 mmol, 1.00 eq.) and ethyl 2-diethoxyphosphorylacetate (669 mg, 2.98 mmol, 592 μL, 2.00 eq.) in DMF (3.00 mL) was added NaH (119 mg, 2.98 mmol, 60% purity, 2.00 eq.) at rt under a nitrogen atmosphere. The resultant mixture was stirred at 40° C. for 12 h. The reaction mixture was diluted with ethyl acetate (50.0 mL) and quenched with water (10.0 mL). The combined organic phase was washed with brine (30.0 mL×3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 4/1) to afford ethyl (E)-3-(2-bromo-6-hydroxy-phenyl)prop-2-enoate (380 mg, 1.37 mmol, 92.0% yield, 98.0% purity) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ=8.02 (d, J=16.0 Hz, 1H), 7.15 (dd, J=1.2, 8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.97 (d, J=16.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.56 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).

To a solution of ethyl (E)-3-(2-bromo-6-hydroxy-phenyl)prop-2-enoate (380 mg, 1.37 mmol, 1.00 eq.) in THF (5.00 mL) and water (5.00 mL) was added NaOAc (225 mg, 2.75 mmol, 2.00 eq.) and 4-methylbenzenesulfonohydrazide (512 mg, 2.75 mmol, 2.00 eq.). The mixture was stirred at 70° C. for 12 h. The mixture was cooled to rt and extracted with ethyl acetate (20.0 mL×2). The combined organic phase was washed with brine (30.0 mL×3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=20/1 to 10/1) to afford ethyl 3-(2-bromo-6-hydroxy-phenyl)propanoate (380 mg, 1.32 mmol, 96.2% yield, 95.0% purity) as a light-yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=8.27 (s, 1H), 7.14 (dd, J=1.2, 8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.93-6.88 (m, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.50 (s, 1H), 3.10-3.03 (m, 2H), 2.87-2.79 (m, 2H), 1.28-1.24 (m, 3H).

To a solution of ethyl 3-(2-bromo-6-hydroxy-phenyl)propanoate (0.10 g, 348 μmol, 1.00 eq.) in THF (2.00 mL) was added LAH (39.6 mg, 1.04 mmol, 3.00 eq.) at 0° C. The mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (0.50 mL) and was diluted with DCM (30.0 mL). The mixture was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by prep-TLC (SiO₂, PE:EA=2:1) to afford 3-bromo-2-(3-hydroxypropyl)phenol (70.0 mg, 297 μmol, 85.4% yield, 98.0% purity) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.66 (br s, 1H), 7.14 (dd, J=1.2, 8.0 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.84 (dd, J=1.2, 8.0 Hz, 1H), 3.64 (t, J=5.6 Hz, 2H), 3.03-2.94 (m, 2H), 2.01-1.90 (m, 2H).

Iodine (3.30 g, 13.0 mmol, 2.62 mL, 1.65 eq.) was added to a solution of imidazole (2.42 g, 35.5 mmol, 4.50 eq.) and PPh₃ (3.72 g, 14.2 mmol, 1.80 eq.) in DCM (40.0 mL) at 0° C. The reaction mixture was stirred for 15 min followed by the dropwise addition of a solution of 3-bromo-2-(3-hydroxypropyl)phenol (1.85 g, 7.89 mmol, 1.00 eq.) in DCM (10.0 mL). The reaction mixture was protected from light and stirred for 12 h at rt. The mixture was diluted with DCM (50.0 mL) and washed with brine (40.0 mL×2). The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 20/1) to afford 3-bromo-2-(3-iodopropyl)phenol (2.10 g, 6.16 mmol, 78.1% yield) as a white solid.

To a solution of 3-bromo-2-(3-iodopropyl)phenol (2.10 g, 6.16 mmol, 1.00 eq.) in acetone (50.0 mL) was added K₂CO₃ (1.70 g, 12.3 mmol, 2.00 eq.). The mixture was stirred at 50° C. for 12 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO₂, petroleum ether) to afford 5-bromochromane (1.20 g, 5.63 mmol, 91.5% yield, 100% purity) as a light-yellow oil.

A mixture of 5-bromochromane (0.10 g, 469 μmol, 1.00 eq.), Zn(CN)₂ (110 mg, 939 μmol, 2.00 eq.), Pd(PPh₃)₄ (81.4 mg, 70.4 μmol, 0.15 eq.) in DMAC (1.00 mL) was purged with nitrogen. The mixture was stirred at 100° C. for 8 h. The reaction mixture was diluted with ethyl acetate (20.0 mL) and washed with brine (15.0 mL×3). The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by prep-TLC (SiO₂, PE:EA=10:1) to afford chromane-5-carbonitrile (60.0 mg, 377 μmol, 80.3% yield) as a light-yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.22-7.18 (m, 1H), 7.18-7.13 (m, 1H), 7.02 (dd, J=1.2, 8.0 Hz, 1H), 4.28-4.19 (m, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.16-2.02 (m, 2H).

To a solution of chromane-5-carbonitrile (60.0 mg, 377 μmol, 1.00 eq.) in THF (3.00 mL) was added LAH (57.2 mg, 1.51 mmol, 4.00 eq.) at 0° C. The mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (1.00 mL) and diluted with DCM (30 mL). The mixture was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford chroman-5-ylmethanamine (70.0 mg, crude) as a light-yellow oil.

A seventh exemplary Intermediate B, Intermediate B-7, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond, one R³ is fluorine and two methylene hydrogens are replaced with deuteriums.

To a solution of 5-fluorobenzofuran-4-carbonitrile (2.00 g, 12.4 mmol, 1.00 equiv) in dimethyl sulfoxide (20.0 mL) was added hydrogen peroxide (7.04 g, 62.1 mmol, 5.96 mL, 30% purity, 5.00 equiv) and potassium carbonate (1.72 g, 12.4 mmol, 1.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 h. The residue was poured into ice-water (5.00 mL) and stirred for 10 min. The mixture was filtered and concentrated under vacuum to give 5-fluorobenzofuran-4-carboxamide (1.80 g, 10.1 mmol, 81.0% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.11 (d, J=2.0 Hz, 1H), 7.81 (br s, 1H), 7.73 (dd, J=4.0, 8.8 Hz, 2H), 7.23 (dd, J=9.2, 10.4 Hz, 1H), 7.10 (d, J=1.2 Hz, 1H).

A solution of 5-fluorobenzofuran-4-carboxamide (1.80 g, 10.1 mmol, 1.00 equiv) in methyl alcohol (4.00 mL) was charged with hydrogen (50 psi) and Pd/C (500 mg, 50% purity). The mixture was stirred at 35° C. for 12 h. The mixture was filtered and concentrated under vacuum to give 5-fluoro-2,3-dihydrobenzofuran-4-carboxamide (1.60 g, 8.83 mmol, 87.9% yield) as a white solid. LCMS [M+1]: 182.2.

¹H NMR (400 MHz, DMSO-d₆) δ=7.82-7.55 (m, 2H), 6.96 (t, J=8.8 Hz, 1H), 6.79 (dd, J=4.0, 8.8 Hz, 1H), 4.54 (t, J=8.8 Hz, 2H), 3.25 (t, J=8.8 Hz, 2H).

To a solution of 5-fluoro-2,3-dihydrobenzofuran-4-carboxamide (1.60 g, 8.83 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added lithium aluminumdeuteride (670 mg, 17.7 mmol, 911 μL, 2.00 equiv) at 0° C. The mixture was stirred at 60° C. for 12 h. The mixture was quenched with water (1.60 mL) (stirred for 15 min), followed by sodium hydroxide (1.50 mL, 15% aq.) (15 min) and water (4.80 mL) (30 min). The suspension was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (basic conditions) to afford (5-fluoro-2,3-dihydrobenzofuran-4-yl)methan-d2-amine (0.80 g, 4.56 mmol, 51.6% yield, 96.4% purity) as a red oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.82-6.76 (m, 1H), 6.59 (dd, 8.8 Hz, 1H), 4.59 (t, J=8.8 Hz, 2H), 3.23 (t, J=8.8 Hz, 2H).

An eighth exemplary Intermediate B, Intermediate B-8, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond, one R³ is fluorine, two methylene hydrogens and two hydrogens on the benzofuran ring are replaced with deuteriums.

To a solution of 5-fluorobenzofuran-4-carbonitrile (100 mg, 620 μmol, 1.00 equiv) in methanol-d₄ (1.00 mL) was added di-tert-butyl dicarbonate (135 mg, 620 μmol, 143 μL, 1.00 equiv) and palladium on carbon (100 mg, 10.0 w %, 0.09 equiv). The mixture was stirred at 35° C. for 12 h under a deuterium gas atmosphere (15 psi). The reaction was filtered and concentrated at reduced pressure to give tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl-2,3-d2)methyl-d2)carbamate (45.0 mg, 166 μmol, 26.7% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=6.82-6.76 (m, 1H), 6.62 (dd, J=3.6, 8.4 Hz, 1H), 4.86 (br s, 1H), 4.57 (br d, J=10.0 Hz, 1H), 3.27 (br d, J=6.8 Hz, 1H), 1.46-1.41 (s, 9H).

To a solution of tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl-2,3-d2)methyl-d2)carbamate (40.0 mg, 147 μmol, 1.00 equiv) in dichloromethane (2.00 mL) was added trifluoroacetic acid (109 μL, 1.47 mmol, 10.0 equiv). The mixture was stirred at 25° C. for 1 h. and subsequently was concentrated at reduced pressure to give a residue. The residue was added to saturated sodium bicarbonate (2.00 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (2.00 mL×3). The combined organic phase was washed with brine (2.00 mL×3), dried with anhydrous sodium sulfate, filtered and concentrated at reduced pressure to afford dideuterio-(2,3-dideuterio-5-fluoro-2,3-dihydrobenzofuran -4-yl)methanamine (25.0 mg, crude) as a white solid, which was used without further purification.

A ninth exemplary Intermediate B, Intermediate B-9, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O,

is a single bond, and one R³ is fluorine.

To a solution of 5-fluoro-1,3-benzodioxole (500 mg, 3.57 mmol, 1.00 equiv) in THF (5.00 mL) was added n-BuLi (2.50 M, 1.57 mL, 1.10 equiv) dropwise at −78° C. The mixture was stirred at −78° C. for 15 min followed by the dropwise addition of DMF (235 mg, 3.21 mmol, 247 μL, 0.90 equiv) and continued stirring at −78° C. for 0.5 h. The mixture was poured into saturated ammonium chloride aqueous solution (5.00 mL) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (6.00 mL×2). The combined organic phase was washed with brine (6.00 mL×3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-fluoro-1,3-benzodioxole-4-carbaldehyde (370 mg, 2.20 mmol, 61.7% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.07 (s, 1H), 7.12 (dd, J=4.4, 8.4 Hz, 1H), 6.72 (dd, J=8.8, 11.6 Hz, 1H), 6.17 (s, 2H).

To a solution of 5-fluoro-1,3-benzodioxole-4-carbaldehyde (200 mg, 1.19 mmol, 1.00 equiv) in ethyl alcohol (6.00 mL) was added hydroxylamine-hydrochloride (248 mg, 3.57 mmol, 3.00 equiv) and triethylamine (827 μL, 5.95 mmol, 5.00 equiv). The mixture was stirred at 15° C. for 0.5 h and the mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water (3.00 mL×2) and filtered, the filter cake was collected and dried under reduced pressure to give 5-fluoro-1,3-benzodioxole-4-carbaldehyde oxime (200 mg, 1.09 mmol, 91.8% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=11.68 (s, 1H), 8.08 (s, 1H), 6.91 (br dd, J=4.0, 8.4 Hz, 1H), 6.77-6.65 (m, 1H), 6.12 (s, 2H).

To a solution of 5-fluoro-1,3-benzodioxole-4-carbaldehyde oxime (280 mg, 2.07 mmol, 1.00 equiv) in methyl alcohol (3.00 mL) was added Pd/C (2.07 mmol, 10% purity, 1.00 equiv) and di-tert-butyl dicarbonate (906 mg, 4.15 mmol, 953 μL, 2.00 equiv). The mixture was stirred at 25° C. for 12 h under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 2/1) to afford tert-butyl N-[(5-fluoro-1,3-benzodioxol-4-yl)methyl]carbamate (350 mg, 1.71 mmol, 82.3% yield) as a white solid. LCMS [M-55]: 214.1.

To a solution of tert-butyl ((5-fluorobenzo[d][1,3]dioxol-4-yl)methyl)carbamate (85.0 mg, 316 μmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.30 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was neutralized with saturated aq potassium carbonate (5.00 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (5.00 mL×2). The combined organic phase was washed with brine (5.00 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (5-fluorobenzo[d][1,3]dioxol-4-yl)methanamine (45.0 mg, 266 μmol, 84.3% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=6.63 (dd, J=4.4, 8.4 Hz, 1H), 6.52 (dd, J=8.4, 10.4 Hz, 1H), 6.00 (s, 2H), 3.89 (s, 2H).

An exemplary Intermediate C, Intermediate C-1, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine. A mixture of ethyl 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carboxylate (380 mg, 1.25 mmol, 1.00 equiv), (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (250.34 mg, 1.50 mmol, 1.20 equiv), DIEA (322 mg, 2.50 mmol, 434 uL, 2.00 equiv) in DMF (3.00 mL) was purged with nitrogen and was stirred at 85° C. for 0.5 h. To this mixture was added water (10.0 mL) and ethyl acetate (8.00 mL). The biphasic mixture was filtered to remove a solid impurity and the organic layer was concentrated in vacuo to provide ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (443 mg, 1.02 mmol, 81.5% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.87 (s, 1H), 8.50 (t, J=4.8 Hz, 1H), 7.90 (s, 1H), 6.93 (t, J=9.6 Hz, 1H), 6.69 (dd, J=4.0, 8.8 Hz, 1H), 4.65 (d, J=4.8 Hz, 2H), 4.52 (t, J=8.8 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.25 (t, J=8.8 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).

A second exemplary Intermediate C, Intermediate C-2, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR¹¹,

is a double bond and one R³ is fluorine. A mixture of 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carboxylate (160 mg, 525 μmol, 1.00 equiv), (5-fluorobenzofuran-4-yl)methanamine (116 mg, 630 μmol, 1.20 equiv) and DIEA (136 mg, 1.05 mmol, 183 uL, 2.00 equiv) in DMF (2.00 mL) was stirred at 85° C. for 0.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 0/1 to 2/1) to afford ethyl 8-bromo-5-(((5-fluorobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (180 mg, 78.2% yield) as a brown solid. LCMS [M+1]: 433.1.

1H NMR (400 MHz, CD₃OD) δ=8.63 (s, 1H), 7.92 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.45 (dd, J=3.6, 8.8 Hz, 1H), 7.13-7.07 (m, 1H), 7.06 (d, J=1.2 Hz, 1H), 5.04 (s, 2H), 4.38 (q, J=6.8 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).

A third exemplary Intermediate C, Intermediate C-3, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, and

is a single bond. To a solution of ethyl 8-bromo-5-chloro-imidazo[1,2-c] pyrimidine -2-carboxylate (103 mg, 328 μmol, 1.00 equiv), 1,3-benzodioxol-4-ylmethanamine (54.6 mg, 361 μmol, 1.10 equiv) in DMF (2.00 mL) was added DIEA (42.4 mg, 328 μmol, 57.2 uL, 1.00 equiv). The resultant mixture was stirred at 85° C. for 1 h and was subsequently concentrated to afford the crude material. The residue was washed with water (3.00 mL×2) to provide ethyl 5-((benzo[d][1,3]dioxol-4-ylmethyl)amino)-8-bromoimidazo[1,2-c]pyrimidine-2-carboxylate (120 mg, 286.24 μmol, 87.2% yield) as a brown solid. LCMS: [M+1] 421.2.

¹H NMR (400 MHz, DMSO-d₆) δ=8.87 (s, 1H), 8.65 (br s, 1H), 7.88 (s, 1H), 6.90-6.77 (m, 3H), 6.03 (s, 2H), 4.66 (d, J=4.8 Hz, 2H), 4.36-4.31 (m, 2H), 1.33 (t, J=7.2 Hz, 3H).

A fourth exemplary Intermediate C, Intermediate C-4, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is chlorine. To a solution of ethyl 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carboxylate (230 mg, 755 μmol, 1.00 equiv), (5-chloro-2,3-dihydrobenzofuran-4-yl)methanamine (118 mg, 642 μmol, 0.850 equiv) in DMF (2.00 mL) was added DIEA (195 mg, 1.51 mmol, 263 μL, 2.00 equiv) and the reaction mixture was stirred at 85° C. for 1 h. The solution was concentrated in vacuo to give the crude material, which was purified by prep-TLC (petroleum ether/ethyl acetate=1/1) to afford ethyl 8-bromo-5-(((5-chloro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (320 mg) as a brown solid. LCMS: [M+3] 453.1.

Another Intermediate C, Intermediate C-4A, may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R¹¹)₂, and

is a single bond. To a solution of ethyl 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carboxylate (250 mg, 802 μmol, 1.00 eq.) in DMF (3.00 mL) was added DIPEA (207 mg, 1.60 mmol, 279 μL, 2.00 eq.) and chroman-5-ylmethanamine (170 mg, 1.04 mmol, 1.30 eq.). The mixture was stirred at 85° C. for 30 min. The reaction mixture was diluted with water (40 mL) and filtered. The solid was dried under vacuum to afford ethyl 8-bromo-5-((chroman-5-ylmethyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (320 mg, 742 μmol, 92.5% yield) as a yellow solid. LC-MS: [M+1] 433.3.

Yet another exemplary Intermediate C, Intermediate C-4B, may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine. To a solution of (5-fluorobenzothiophen-4-yl)methanamine (39.4 mg, 218 μmol, 1.40 eq.) and 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carbonitrile (40.0 mg, 155 μmol, 1.00 eq.) in DMF (2.00 mL) was added DIEA (60.2 mg, 466 μmol, 81.2 μL, 3.00 eq.). The reaction mixture was stirred at 85° C. for 1 h. The mixture was diluted with ethyl acetate (10.0 mL), washed with brine (10.0 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude residue. The crude material was purified by prep-TLC (petroleum ether/ethyl acetate=1/1) to give 8-bromo-5-((5-fluorobenzo[b]thiophen-4-yl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (35.0 mg, 87.0 μmol, 56.0% yield) as a brown solid. LCMS [M+1]: 404.0.

A fifth exemplary Intermediate C, Intermediate C-5, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine. A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (160 mg, 367 μmol, 1 equiv) and sodium hydroxide (1 M, 1.10 mL, 3 equiv) in methanol (3.30 mL) was stirred at 55° C. for 0.5 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo and the residue was diluted with water (1.00 mL). The pH was adjusted to pH=2 with HCl (1 M) and the solid was collected by filtration. The resultant solid was dried under reduced pressure to afford 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid (124 mg, 304 μmol, 82.8% yield) as a white solid. LC-MS: [M+1] 408.8.

A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid (124 mg, 304 μmol, 1.00 equiv), ammonium chloride (48.8 mg, 913 μmol, 3.00 equiv), HATU (173 mg, 1.50 equiv), DIEA (314 mg, 2.44 mmol, 424 uL, 8 equiv) in DMF (1.00 mL) was stirred at 30° C. for 1 h under an atmosphere of nitrogen. Subsequently, the mixture was concentrated in vacuo. To the crude material was added water (1.00 mL) and the resultant solid was collected by filtration. The solid was dried under reduced pressure to provide 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxamide (100 mg) as a white solid, which was used without further purification.

To a mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxamide (100 mg, 246. μmol, 1.00 equiv), TEA (484 mg, 4.79 mmol, 666 uL, 19.4 equiv) in THF (2.00 mL) was added TFAA (302 mg, 1.44 mmol, 200 uL, 5.84 equiv) at 0° C. Subsequently, the mixture was stirred at 0-30° C. for 40 min under an atmosphere of nitrogen. The mixture was concentrated to provide the crude residue, which was purified by column chromatography (petroleum ether/ethyl acetate, 5/1 to 0/1) to afford 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (100 mg, 245 μmol, 99.7% yield) as a yellow solid. LC-MS: [M+1] 387.8.

Alternatively, Intermediate C-5 may be prepared as follows:

To a solution of 8-bromo-5-chloro-imidazo[1,2-c]pyrimidine-2-carbonitrile (3.00 g, 11.7 mmol, 1.00 equiv) and (5-fluoro-2,3-dihydrobenzofuran-4-yl) methanamine (2.14 g, 12.8 mmol, 1.10 equiv) in DMF (30.0 mL) was added DIEA (3.01 g, 23.3 mmol, 4.06 mL, 2.00 equiv). The resultant mixture was stirred at 85° C. for 1 h, cooled to rt, and poured into water (100 mL). The mixture was extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (50.0 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to afford 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (4.00 g, 10.3 mmol, 88.4% yield) as a yellow solid. LCMS [M+1]: 390.1.

A sixth exemplary Intermediate C, Intermediate C-6, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond and one R³ is fluorine.

A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (204 mg, 460 μmol, 1.00 equiv), di-tert-butyl dicarbonate (201 mg, 919 μmol, 2.00 equiv), 4-(dimethylamino)pyridine (561 ug, 4.60 μmol, 0.01 equiv) in tetrahydrofuran (2.00 mL) was purged with nitrogen and subsequently allowed to stir at 25° C. for 2 h under an atmosphere of nitrogen. The mixture was diluted with water (3.00 mL) and extracted with ethyl acetate (2.00 mL×3). The combined organic layers were washed with brine (2.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. The crude material was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate, 3/1) to afford ethyl 8-bromo-5-((tert-butoxycarbonyl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (160 mg, 198 μmol, 43.0% yield, 66.2% purity) as a white solid. LC-MS [M+1]: 537.2.

¹H NMR (400 MHz, CDCl₃) δ=8.11 (s, 1H), 7.93 (s, 1H), 6.67-6.61 (m, 1H), 6.59-6.54 (m, 1H), 5.08 (s, 2H), 4.58 (t, J=8.8 Hz, 2H), 4.47 (q, J=7.2 Hz, 2H), 3.32 (br t, J=8.8 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.36 (s, 9H).

A seventh exemplary Intermediate C, Intermediate C-7, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond, one R³ is fluorine and two methylene hydrogens are replaced with deuteriums.

To a solution of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methan-d2-amine (50.0 mg, 284 μmol, 1.00 equiv), 8-bromo-5-chloroimidazo[1,2-c]pyrimidine-2-carbonitrile (73.1 mg, 284 μmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA (110 mg, 851 μmol, 148 μL, 3.00 equiv). The mixture was stirred at 85° C. for 1 h. The reaction mixture was diluted with water (1.00 mL) and extracted with ethyl acetate (1.00 mL×3). The combined organic layer was washed with brine (3.00 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl-d2)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (20.0 mg, crude) as a white solid. LCMS [M+1]: 390.0.

An eighth exemplary Intermediate C, Intermediate C-8, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R¹¹)₂,

is a single bond, one R³ is fluorine, two methylene hydrogens and two hydrogens on the benzofuran ring are replaced with deuteriums.

To a solution of dideuterio-(2,3-dideuterio-5-fluoro-2,3-dihydrobenzofuran -4-yl)methanamine (31.9 mg, 186 μmol, 1.20 equiv) and 8-bromo-5-chloroimidazo[1,2-c]pyrimidine-2-carbonitrile (40.0 mg, 155 μmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA (108 uL, 621 μmol, 4.00 equiv) and the mixture was stirred at 85° C. for 0.5 h. The mixture was concentrated at reduced pressure to give a residue, which was poured into water (3.00 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3.00 mL×3). The combined organic phase was washed with brine (3.00 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl-2,3-d₂)methyl-d₂)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (25.0 mg, 63.7 μmol, 41.0% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=8.30 (s, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 6.83-6.76 (m, 1H), 6.64 (dd, J=4.0, 8.8 Hz, 1H), 4.59 (br d, J=10.0 Hz, 1H), 3.33 (br d, J=8.4 Hz, 1H).

A ninth exemplary Intermediate C, Intermediate C-9, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O,

is a single bond, and one R³ is fluorine.

To a solution of 8-bromo-5-chloroimidazo[1,2-c]pyrimidine-2-carbonitrile (40.0 mg, 155 μmol, 1.00 equiv) and (5-fluorobenzo[d][1,3]dioxol-4-yl)methanamine (31.5 mg, 186 μmol, 1.20 equiv) in DMF (0.50 mL) was added DIEA (54.1 μL, 310 μmol, 2.00 equiv). The mixture was stirred at 85° C. for 0.5 h under a nitrogen atmosphere. The mixture was poured into water (3.00 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3.00 mL×2). The combined organic phase was washed with brine (3.00 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo-54(5-fluorobenzo[d][1,3]dioxol-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (50.0 mg, 128 μmol, 82.5% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.92 (s, 1H), 8.567 (br s, 1H), 7.95 (s, 1H), 6.88 (dd, J=4.4, 8.4 Hz, 1H), 6.69 (dd, J=8.8, 10.4 Hz, 1H), 6.04 (s, 2H), 4.67 (br d, J=2.0 Hz, 2H).

An exemplary Intermediate D, Intermediate D-1, may be used to synthesize compounds of formula I wherein R¹ is a disubstituted heteroaryl.

A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (370 mg, 1.78 mmol, 1.00 equiv), 2-iodopropane (907 mg, 5.33 mmol, 533 uL, 3.00 equiv) and cesium carbonate (2.32 g, 7.11 mmol, 4.00 equiv) in acetonitrile (7.00 mL) was purged with nitrogen and subsequently stirred at 90° C. for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 1/0 to 3/1) to afford a mixture of 1-isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol e (170 mg, 34.4% yield, 90.0% purity) and 1-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) as a light yellow oil. LCMS [M+1]: 251.4.

¹H NMR (400 MHz, CDCl₃) δ=7.73 (s, 0.6H), 7.65 (s, 1H), 4.50-4.36 (m, 2H), 2.45 (s, 2H), 2.40 (s, 3H), 1.50-1.44 (m, 12H), 1.31 (s, 22H).

A second exemplary Intermediate D, Intermediate D-2, may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with two R⁴ substituents. A mixture of 5-bromo-2-methoxy-4-methyl-pyridine (350 mg, 1.73 mmol, 1.00 equiv), bis(pinacolato)diboron (2.20 g, 8.66 mmol, 5.00 equiv), potassium acetate (527 mg, 5.37 mmol, 3.10 equiv), Pd(dppf)Cl₂ (127 mg, 173 μmol, 0.10 equiv) in dioxane (5.00 mL) was purged with nitrogen and stirred at 90° C. for 3 h. The residue was diluted with ethyl acetate (3.00 mL) and extracted with ethyl acetate (2.00 mL×3). The combined organic layers were washed with brine (2.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 100/1 to 20/1) to afford 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (150 mg, 546 μmol, 31.5% yield, 90.6% purity) as a white solid.

¹H NMR (400 Mhz, CDCl₃) δ=8.47 (s, 1H), 6.51 (s, 1H), 3.93 (s, 3H), 2.45 (s, 3H), 1.33 (s. 12H).

A third exemplary Intermediate D, Intermediate D-3, may be used to synthesize compounds of formula I or formula II wherein R¹ is heteroaryl substituted with two R⁴ substituents. A mixture of cyclopropanecarboxamidine-HCl (5.00 g, 59.4 mmol, 1.00 equiv), ethyl 3-oxobutanoate (7.74 g, 59.4 mmol, 7.51 mL, 1.00 equiv), sodium ethoxide (8.09 g, 119 mmol, 2.00 equiv) in ethanol (500 mL) was purged with nitrogen and subsequently stirred at 25° C. for 12 h. The residue was dissolved in water (25.0 mL) and the pH was adjusted to -4 with HCl (1 M). After cooling to 5° C., the solid was collected and dried under reduced pressure to give 2-cyclopropyl-6-methyl-pyrimidin-4-ol (4.00 g, 26.6 mmol, 44.8% yield, 100% purity) as a white solid. LC-MS [M+1]: 151.3.

¹H NMR (400 Mhz, DMSO-d₆) δ=12.45 (s, 1H), 5.93 (s, 1H), 2.07 (s, 3H), 1.90-1.85 (m, 1H), 1.00-0.97 (m, 4H).

A mixture of 2-cyclopropyl-6-methyl-pyrimidin-4-ol (4.00 g, 26.6 mmol, 1.00 equiv), bromine (4.34 g, 27.2 mmol, 1.40 mL, 1.00 equiv), potassium hydroxide (1.49 g, 26.6 mmol, 1.00 equiv) in water (32.6 mL) was stirred at 25° C. for 2 h under a nitrogen atmosphere. The solid was filtered to give 5-bromo-2-cyclopropyl-6-methyl-pyrimidin-4-ol (2.76 g, 9.31 mmol, 35.0% yield, 77.3% purity) as a white solid. LC-MS [M+3]: 231.0.

A mixture of 5-bromo-2-cyclopropyl-6-methyl-pyrimidin-4-ol (2.50 g, 8.44 mmol, 1.00 equiv) and dimethyl formamide (1.54 g, 21.1 mmol, 1.62 mL, 2.50 equiv) in toluene (36.9 mL) was added dropwise a solution of phosphorus oxychloride (1.57 g, 10.2 mmol, 951 uL, 1.21 equiv) in toluene (9.20 mL) at 0° C. The mixture was subsequently stirred at 25° C. for 3 h under a nitrogen atmosphere. The mixture was poured into sodium carbonate (1.00 M, 55.2 mL) and extracted with ethyl acetate (10.0 mL×3). The combined organic phase was concentrated to afford compound 5-bromo-4-chloro-2-cyclopropyl-6-methyl-pyrimidine (2.31 g, 4.51 mmol, 53.5% yield, 48.4% purity) as a yellow oil. LC-MS [M+3]: 249.1.

A mixture of 5-bromo-4-chloro-2-cyclopropyl-6-methyl-pyrimidine (2.31 g, 9.33 mmol, 1.00 equiv), 4-methylbenzenesulfonohydrazide (5.91 g, 31.7 mmol, 3.40 equiv) in chloroform (4.30 mL) was stirred at 90° C. for 16 h under a nitrogen atmosphere. The solid was filtered and rinsed with dichloromethane (20.0 mL) to afford N-(5-bromo-2-cyclopropyl-6-methyl-pyrimidin-4-yl)-4-methyl-benzenesulfonohydrazide (1.60 g, 4.02 mmol, 43.1% yield, 99.8% purity) as a white solid. LC-MS [M+3]: 399.2.

¹H NMR (400 MHz, DMSO-d₆) δ=10.08 (br s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 2.44 (br s, 3H), 2.37 (s, 3H), 2.05-1.83 (m, 1H), 1.05-0.90 (m, 2H), 0.87-0.75 (m, 2H).

A mixture of N′-(5-bromo-2-cyclopropyl-6-methyl-pyrimidin-4-yl)-4-methyl-benzenesulfonohydrazide (1.60 g, 4.02 mmol, 1.00 equiv) and aqueous sodium carbonate (0.57 M, 90.6 mL, 12.8 equiv) was stirred at 90° C. for 1 h under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (50.0 mL) and the organic phase was separated and concentrated to afford 5-bromo-2-cyclopropyl-4-methyl-pyrimidine (620 mg, 2.59 mmol, 64.6% yield, 89.2% purity) as a brown oil. LC-MS [M+1]: 213.2.

¹H NMR (400 MHz, CDCl₃) δ=8.49 (s, 1H), 2.56 (s, 3H), 2.25-2.08 (m, 1H), 1.19-0.99 (m, 4H).

A mixture of 5-bromo-2-cyclopropyl-4-methyl-pyrimidine (580 mg, 2.43 mmol, 1.00 equiv),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (863 mg, 3.40 mmol, 1.40 equiv), potassium acetate (715 mg, 7.28 mmol, 3.00 equiv), and Pd(dppf)Cl₂ (88.8 mg, 121 μmol, 0.05 equiv) in dioxane (5.00 mL) was purged with nitrogen and was subsequently stirred at 90° C. for 4 h under a nitrogen atmosphere. The residue was diluted with water (3.00 mL) and extracted with ethyl acetate (2.00 mL×3). The combined organic layers were washed with brine (2.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 100/1 to 10/1) to afford 2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.00 g, 1.92 mmol, 79.2% yield, 50.0% purity) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=8.73 (s, 1H), 2.62 (s, 3H), 2.27-2.14 (m, 1H), 1.34 (s, 12H), 1.18-1.13 (m, 2H), 1.07-1.01 (m, 2H).

A fourth exemplary Intermediate D, Intermediate D-4, may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with two R⁴ substituents. A mixture of sodium (111 mg, 4.82 mmol, 1.00 equiv) in methanol (772 mg, 24.1 mmol, 975. μL, 5.00 equiv) was stirred at 25° C. for 0.5 h. To this solution was added 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) and the mixture was stirred at 25° C. for 2 h. The reaction was quenched upon the addition of water (5 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL×3) and the combined organic phase was washed with brine (10.0 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford 5-bromo-2-methoxy-4-methyl-pyrimidine (500 mg, 2.46 mmol, 51.1% yield) as a red oil. LCMS: [M+1] 203.1.

To a solution of 5-bromo-2-methoxy-4-methyl-pyrimidine (500 mg, 2.46 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (813 mg, 3.20 mmol, 1.30 equiv) and potassium acetate (483 mg, 4.93 mmol, 2.00 equiv) in dioxane (5.00 mL) was added Pd(dppf)Cl₂ (180 mg, 246 μmol, 0.10 equiv) under nitrogen. The resultant mixture was stirred at 105° C. for 2 h. The mixture was concentrated in vacuo to give the crude material, which was purified by column chromatography (petroleum ether/ethyl acetate, 1/0 to 1:1) to afford 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (150 mg, 539 μmol, 21.9% yield, 90.0% purity) as a red oil.

¹H NMR (400 MHz, MeOD) δ=8.69 (s, 1H), 4.03 (s, 3H), 2.65 (s, 3H), 1.38 (s, 12H).

A fifth exemplary Intermediate D, Intermediate D-5, may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with two R⁴ substituents. To a solution of isopropanol (869 mg, 14.5 mmol, 1.11 mL, 3.00 equiv) in THF (10.0 mL) was added portionwise NaH (578 mg, 14.5 mmol, 60.0% purity, 3.00 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Subsequent to the addition of 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) the mixture was allowed to stir at 25° C. for 3 h. The mixture was poured into water (20.00 mL) and the aqueous phase was extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (20.0 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated to provide 5-bromo-2-isopropoxy-4-methyl-pyrimidine (600 mg, 2.60 mmol, 53.9% yield) as a yellow oil.

To a solution of 5-bromo-2-isopropoxy-4-methyl-pyrimidine (300 mg, 1.30 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (429 mg, 1.69 mmol, 1.30 equiv) and potassium acetate (255 mg, 2.60 mmol, 2.00 equiv) in dioxane (5.00 mL) was added Pd(dppf)Cl₂ (95.0 mg, 130 μmol, 0.10 equiv). The mixture was stirred at 105° C. for 2 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to provide the crude material, which was purified by column chromatography (petroleum ether/ethyl acetate, 1/1 to dichloromethane:methanol, 10/1) to afford 2-isopropoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (60.0 mg, 216 μmol, 16.6% yield) as a white oil. LCMS: [M+1] 279.3.

A sixth exemplary Intermediate D, Intermediate D-6, may be used to synthesize compounds of formula I, wherein R¹ is aryl substituted with two R⁴ substituents. To a solution of 1-bromo-4-fluoro-2-methyl-benzene (1.00 g, 5.29 mmol, 1.00 equiv) in DMF (10.0 mL) was added NaSMe (869 mg, 5.29 mmol, 1.00 equiv). The mixture was stirred at 50° C. for 12 h. The reaction mixture was diluted with ethyl acetate (50.0 mL) and the organic layer was washed with brine (40.0 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-bromo-2-methyl-4-methylsulfanyl-benzene (900 mg, crude) as a light yellow oil.

¹H NMR (400 MHz, MeOD) δ=7.42 (d, J=8.4 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 6.97 (dd, J=2.0, 8.4 Hz, 1H), 2.45 (s, 3H), 2.35 (s, 3H).

To a solution of 1-bromo-2-methyl-4-methylsulfanyl-benzene (900 mg, 4.15 mmol, 1.00 equiv) in DCM (9.00 mL) was added m-CPBA (1.43 g, 8.29 mmol, 2.00 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with DCM (20.0 mL), washed with satd aq potassium carbonate (20.0 mL×3), brine (20.0 mL×2), and the organic phase was concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 1/0 to 3/1) to afford 1-bromo-2-methyl-4-methylsulfonyl-benzene (370 mg, 1.41 mmol, 34.0% yield, 95.0% purity) as a white solid.

¹H NMR (400 MHz, MeOD) δ=7.87 (d, J=1.6 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.66 (dd, J=2.0, 8.4 Hz, 1H), 3.12 (s, 3H), 2.50 (s, 3H).

A mixture of 1-bromo-2-methyl-4-methylsulfonyl-benzene (170 mg, 648 μmol, 1.00 equiv), potassium acetate (127 mg, 1.30 mmol, 2.00 equiv), Pd(dppf)Cl₂ (47.4 mg, 64.8 μmol, 0.100 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (247 mg, 972 μmol, 1.50 equiv) in dioxane (3.00 mL) was purged with nitrogen. The resultant reaction mixture was stirred at 105° C. for 1 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The crude material was purified by prep-TLC (petroleum ether/ethyl acetate, 5/1) to afford 4,4,5,5-tetramethyl-2-(2-methyl-4-methylsulfonyl-phenyl)-1,3,2-dioxaborolane (110 mg, 338 μmol, 52.1% yield, 90.9% purity) as a colorless oil. LCMS [M+1]: 296.9.

A seventh exemplary Intermediate D, Intermediate D-7, may be used to synthesize compounds of formula I, wherein R¹ is aryl substituted with an R⁴ substituent. To a solution of 1-(4-bromophenyl)ethanone (1.00 g, 5.02 mmol, 1.00 equiv), pyrrolidine (1.79 g, 25.1 mmol, 2.10 mL, 5.00 equiv) in methanol (16.0 mL) was added NaBH₃CN (347 mg, 5.53 mmol, 1.10 equiv). The mixture was stirred at 20° C. for 24 h. To the mixture was added water (4.00 mL) and the aqueous phase was extracted with ethyl acetate (5.00 mL). The combined organic phase was washed with brine (2.00 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to afford 1-[1-(4-bromophenyl)ethyl]pyrrolidine (1.00 g, 3.93 mmol, 78.3% yield) as a yellow oil.

To a solution of 1-[1-(4-bromophenyl)ethyl]pyrrolidine (400 mg, 1.57 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (799 mg, 3.15 mmol, 2.00 equiv) and potassium acetate (308 mg, 3.15 mmol, 2.00 equiv) in dioxane (2.00 mL) was added Pd(dppf)Cl₂ (115 mg, 157 μmol, 0.100 equiv). The reaction mixture was stirred at 105° C. for 2 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to give a residue. The crude material was purified by column chromatography (petroleum ether/ethyl acetate, 1/0 to 1/1) to afford 1-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]pyrrolidine (110 mg) as a red oil.

An eighth exemplary Intermediate D, Intermediate D-8, may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with two R⁴ substituents. To a solution of n-butyllithium (2.50 M, 1.80 mL, 1.00 equiv) was added dropwise over one min to i-PrMgCl (2.00 M, 1.12 mL, 0.500 equiv) in THF (12 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 5 min followed by the addition of 5-bromo-4-chloro-2-methoxy-pyridine (1.00 g, 4.50 mmol, 1.00 equiv) after which the mixture was stirred at 0° C. for 45 min. To this solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (836 mg, 4.50 mmol, 917 uL, 1.00 equiv) and the mixture stirred for an additional 15 min prior to stirring at 20° C. for 3 h. The reaction mixture was quenched by the addition of satd aq ammonium chloride (20.0 mL) at 20° C. and was extracted with ethyl acetate (20.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 4-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.00 g, 3.71 mmol, 82.5% yield) as a gray solid, which used for the next step without further purification.

¹H NMR (400 MHz, CDCl₃) δ=8.47 (s, 1H), 6.77 (s, 1H), 3.97 (s, 3H), 1.38 (s, 12H).

A ninth exemplary Intermediate D, Intermediate D-9 may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with three R⁴ substituents. A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol e (100 mg, 450 μmol, 1.00 equiv), isopropyl iodide (306 mg, 1.80 mmol, 180 uL, 4.00 equiv) and cesium carbonate (587 mg, 1.80 mmol, 4.00 equiv) in acetonitrile (3.00 mL) was purged with nitrogen and subsequently stirred at 65° C. for 4 h. The mixture was filtered and the solvent was removed in vacuo to afford 1-isopropyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 368 μmol, 81.8% yield, 97.3% purity) as a green oil. LC-MS [M+1]: 265.

A tenth exemplary Intermediate D, Intermediate D-10, may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with two R⁴ substituents. A mixture of 3-bromo-6-fluoro-2-methyl-pyridine (1.00 g, 5.26 mmol, 1.00 equiv) and N-methylpiperazine (685 mg, 6.84 mmol, 759 μL, 1.30 equiv) was stirred at 110° C. for 12 h. The mixture was diluted with ethyl acetate (50.0 mL), washed with brine (20.0 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated to provide 1-(5-bromo-6-methyl-2-pyridyl)-4-methyl-piperazine (1.10 g, 4.07 mmol, 77.4% yield) as a yellow solid. LCMS [M+1]: 272.1.

To a solution of 1-(5-bromo-6-methyl-2-pyridyl)-4-methyl-piperazine (400 mg, 1.48 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (752 mg, 2.96 mmol, 2.00 equiv) and potassium acetate (291 mg, 2.96 mmol, 2.00 equiv) in dioxane (2.00 mL) was added Pd(dppf)Cl₂ (108 mg, 148 μmol, 0.100 equiv). The reaction was stirred at 105° C. for 2 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to give a residue. The crude material was purified by prep-TLC (DCM/MeOH=10/1) to afford compound 1-methyl-4-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (210 mg, 662 μmol, 44.7% yield) as a brown oil. LCMS [M+1]: 318.3.

An eleventh exemplary Intermediate D, Intermediate D-11, may be used to synthesize compounds of formula I, wherein R¹ is heteroaryl substituted with three R⁴ substituents. To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 450 μmol, 1.00 equiv), (2S)-2-methyloxirane (392 mg, 6.75 mmol, 473 μL, 15.0 equiv) was added cesium carbonate (29.3 mg, 90.1 μmol, 0.20 equiv). The reaction mixture was stirred at 50° C. for 16 h and was subsequently concentrated under vacuum to give a residue. The crude residue was purified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1) to afford (2S)-1-[3,5-dimethyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol (56.0 mg, 44.4% yield) as a yellow oil. LCMS [M+1]: 281.3.

A twelfth exemplary Intermediate D, Intermediate D-12, may be used to synthesize compounds of formula I, wherein R¹ is aryl substituted with two R⁴ substituents. To a solution of 4-bromo-3-chloro-benzoic acid (300 mg, 1.27 mmol, 1.00 equiv), DIEA (490 mg, 3.79 mmol, 660 μL, 3.00 equiv) and N,N-dimethylamine (2.00 M in THF, 1.27 mL, 2.00 equiv) in DMF (3.00 mL) was added HATU (727 mg, 1.91 mmol, 1.50 equiv). The mixture was stirred at room temperature for 2 h and the reaction mixture was subsequently quenched upon the addition water (15.0 mL). The mixture was extracted with dichloromethane (20.0 mL×3). The combined organic layer was washed with water (30.0 mL) and concentrated to provide the crude mixture. The resultant residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=5/1 to 2/1) to afford 4-bromo-3-chloro-N,N-dimethyl-benzamide (430 mg, 983 μmol, 77.0% yield, 60.0% purity) as a white solid. LCMS [M+1]: 264.0.

¹H NMR (400 MHz, CDCl₃) δ=7.67 (d, J=8.2 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.18 (dd, J=2.0, 8.4 Hz, 1H), 3.11 (s, 3H), 2.99 (s, 3H).

To a solution of 4-bromo-3-chloro-N,N-dimethyl-benzamide (150 mg, 343 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (870 mg, 3.43 mmol, 10.0 equiv) and potassium acetate (67.0 mg, 683 μmol, 2.00 equiv) in dioxane (10.0 mL) was added Pd(PPh₃)₂Cl₂ (24.0 mg, 34.2 μmol, 0.10 equiv). The vessel was flushed with nitrogen and the mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and filtered through a pad of Celite. Purification by prep-TLC (SiO₂, petroleum ether/ethyl acetate=2/1) afforded [2-chloro-4-(dimethylcarbamoyl)phenyl]boronic acid (200 mg) as a yellow solid. LCMS [M+1]: 228.0.

A thirteenth exemplary Intermediate D, Intermediate D-13, may be used to synthesize compounds of formula I, wherein R¹ is aryl substituted with two R⁴ substituents. A mixture of 4-bromo-3-methyl-benzaldehyde (500 mg, 2.51 mmol, 1.00 equiv) and N,N-dimethylamine (2 M in THF, 6.3 mL, 12.6 mmol, 5.00 equiv) in methanol (10.0 mL) was stirred at 40° C. for 30 min. Subsequently, sodium triacetoxyborohydride (1.60 g, 7.54 mmol, 3.00 equiv) was added and the mixture was stirred for another 3 h. The solution was concentrated under reduced pressure to give a residue. The crude residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 0/1 then dichloromethane/methanol=20/1 to 10/1) to afford 1-(4-bromo-3-methyl-phenyl)-N,N-dimethyl-methanamine (570 mg) as a brown oil.

¹H NMR (400 MHz, CD₃OD) δ=7.61 (d, J=8.0 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.16 (dd, J=1.6, 8.0 Hz, 1H), 3.96 (s, 2H), 2.63 (s, 6H), 2.42 (s, 3H).

A mixture of 1-(4-bromo-3-methyl-phenyl)-N,N-dimethyl-methanamine (470 mg, 2.06 mmol, 1.00 equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (785 mg, 3.09 mmol, 1.50 equiv), potassium acetate (404 mg, 4.12 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (151 mg, 206 μmol, 0.100 equiv) in dioxane (8.00 mL) was purged with nitrogen and allowed to stir at 105° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (dichloromethane/methanol=50/1 to 10/1) to afford N,N-dimethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (70.0 mg, 185 μmol, 8.99% yield, 72.8% purity) as a brown oil. LCMS [M+1]: 275.6.

A fourteenth exemplary Intermediate D, Intermediate D-14, may be used to synthesize compounds of formula I, wherein R¹ is aryl substituted with one R⁴ substituent. To a solution of 4-bromobenzenesulfonyl chloride (200 mg, 783 μmol, 1.00 equiv) in THF (2.00 mL) was added ammonia (7 N in MeOH, 224 μL, 1.57 mmol, 2.00 equiv). The reaction mixture was stirred at 25° C. for 30 min. The mixture was concentrated in vacuo to provide a residue that was poured into water (10.0 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL×3) and the combined organic phase was washed with brine (3.00 mL×3), dried with anhydrous sodium sulfate, filtered and concentrated to give 4-bromobenzenesulfonamide (180 mg, 762 μmol, 97.4% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.82-7.72 (m, 4H), 7.46 (s, 2H).

To a solution of 4-bromobenzenesulfonamide (100 mg, 424 μmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (129 mg, 508 μmol, 1.20 equiv) in DMSO (2.00 mL) was added potassium acetate (83.1 mg, 847 μmol, 2.00 equiv) and Pd(dppf)Cl₂ (31.0 mg, 42.4 μmol, 0.10 equiv) under an atmosphere of nitrogen. The mixture was stirred at 80° C. for 3 h and was subsequently concentrated under vacuum to give a residue. The residue was poured into water (10.0 mL) and the aqueous phase was extracted with ethyl acetate (10.0 mL×3). The combined organic phase was washed with brine (5.00 mL×3), dried with anhydrous sodium sulfate, filtered and concentrated to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (95.0 mg, 336 μmol, 79.2% yield) as a red solid.

¹H NMR (400 MHz, CDCl₃) δ=7.96-7.88 (m, 4H), 7.26 (s, 2H), 1.35 (s, 12H).

A fifteenth exemplary Intermediate D, Intermediate D-15, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued heteroaryl. To a solution of 2-methoxyethanol (236 mg, 3.10 mmol, 245 μL, 1.50 equiv) in tetrahydrofuran (2.00 mL) was added portionwise sodium hydride (99.3 mg, 60.0%, 2.48 mmol, 1.20 equiv) at 0° C. The mixture was stirred at this temperature for 45 min followed by the dropwise addition of 5-bromo-2-chloro-pyrimidine (400 mg, 2.07 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for an additional 4 h. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=10/1) to afford 5-bromo-2-(2-methoxyethoxy)pyrimidine (150 mg, 644 μmol, 31.1% yield) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ=8.54 (s, 2H), 4.42-4.37 (m, 2H), 3.68-3.62 (m, 2H), 3.30 (s, 3H).

A mixture of 5-bromo-2-(2-methoxyethoxy)pyrimidine (150 mg, 644 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (327 mg, 1.29 mmol, 2.00 equiv), potassium acetate (126 mg, 1.29 mmol, 2.00 equiv), Pd(dppf)Cl₂ (47.1 mg, 64.4 μmol, 0.10 equiv) in dioxane (1.00 mL) was purged with nitrogen stirred at 100° C. for 2 h. The reaction was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=1/1) to afford 2-(2-m ethoxy ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimi dine (130 mg, 464 μmol, 72.1% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=8.83-8.79 (m, 2H), 4.61-4.54 (m, 2H), 3.82-3.76 (m, 2H), 3.44 (s, 3H), 1.36 (s, 12H).

A sixteenth exemplary Intermediate D, Intermediate D-16, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued heteroaryl. To a solution of ethylene glycol (310 mg, 5.00 mmol, 280 μL, 2.00 equiv), 5-bromo-4-methyl-pyridine-2-carbaldehyde (500 mg, 2.50 mmol, 1.00 equiv) in toluene (20.0 mL) was added p-toluenesulfonic acid (47.6 mg, 250 μmol, 0.10 equiv). The mixture was stirred at 110° C. for 12 h and was subsequently concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 5:1) to afford 5-bromo-2-(1,3-dioxolan-2-yl)-4-methylpyridine (320 mg, 1.24 mmol, 49.6% yield) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=8.64 (s, 1H), 7.42 (s, 1H), 5.80 (s, 1H), 4.19-4.14 (m, 2H), 4.10-4.05 (m, 2H), 2.42 (s, 3H).

To a solution of 5-bromo-2-(1,3-dioxolan-2-yl)-4-methylpyridine (300 mg, 1.23 mmol, 1.00 equiv) in diethyl ether (20.0 mL) was added n-butyllithium (2.5 M, 737 μL, 1.50 equiv) at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 0.5 h followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (457 mg, 2.46 mmol, 501 μL, 2.00 equiv). The mixture was warmed to 0° C. and stirred for an additional 1.5 h. The mixture was quenched with water (15.0 mL) and the resulting mixture was extracted with ethyl acetate (20.0 mL×2). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(1,3-dioxolan-2-yl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (150 mg, crude) as a yellow oil. LCMS [M+1]: 292.15.

A seventeenth exemplary Intermediate D, Intermediate D-17, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued bicyclic heteroaryl. A mixture of paraformaldehyde (350 mg, 3.63 mmol, 2.20 equiv) in methanol (1.00 mL) was stirred at 60° C. for 1 h and then cooled to 40° C. To the mixture was added AcOH (1 drop) and 6-bromo-1,2,3,4-tetrahydroisoquinoline (350 mg, 1.65 mmol, 1.00 equiv) followed by NaCNBH₃ (114 mg, 1.82 mmol, 1.1 equiv). The mixture was stirred at 40° C. for 1 h and was subsequently filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=2/1) to afford 6-bromo-2-methyl-3,4-dihydro -1H-isoquinoline (360 mg, 1.59 mmol, 96.5% yield) as a yellow oil.

¹H NMR (400 MHz, CD₃OD) δ=7.32 (s, 1H), 7.28 (dd, J=2.0, 8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.57 (s, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.75-2.72 (m, 2H), 2.46 (s, 3H).

A mixture of 6-bromo-2-methyl-3,4-dihydro-1H-isoquinoline (220 mg, 973 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (494 mg, 1.95 mmol, 2.00 equiv), potassium acetate (191 mg, 1.95 mmol, 2.00 equiv), Pd(dppf)Cl₂ (71.2 mg, 97.3 μmol, 0.10 equiv) in dioxane (3.00 mL) was purged with nitrogen and subsequently stirred at 100° C. for 2 h. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=2/1) to afford 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline (150 mg, crude) as a white solid.

An eighteenth exemplary Intermediate D, Intermediate D-18, may be used to synthesize compounds of formula I, wherein R¹ is a N-protected bicyclic heteroaryl. To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (400 mg, 1.89 mmol, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added Boc₂O (617 mg, 2.83 mmol, 1.50 equiv) and dimethylaminopyridine (46.1 mg, 377 μmol, 0.20 equiv). The mixture was stirred at 25° C. for 3 h and was subsequently filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 3/1) to afford tert-butyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (150 mg, 480 μmol, 25.5% yield) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ=7.38-7.32 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 4.52 (br s, 2H), 3.64 (br t, J=6.0 Hz, 2H), 2.84 (t, J=6.0 Hz, 2H), 1.51 (s, 9H).

A mixture of tert-butyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (140 mg, 448 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (228 mg, 897 μmol, 2.00 equiv), Pd(dppf)Cl₂ (32.8 mg, 44.8 μmol, 0.10 equiv), potassium acetate (88.0 mg, 897 μmol, 2.00 equiv) in dioxane (1.00 mL) was purged with nitrogen and subsequently stirred at 100° C. for 2 h. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=2/1) to afford tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100 mg, 278 μmol, 62.1% yield) as a yellow oil.

¹H NMR (400 MHz, CD₃OD) δ=7.58-7.54 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 4.58 (br s, 2H), 3.65 (br t, J=6.0 Hz, 2H), 2.84 (t, J=6.0 Hz, 2H), 1.35 (s, 12H), 1.19 (br s, 1H), 1.22 (s, 9H).

A nineteenth exemplary Intermediate D, Intermediate D-19, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued aryl. A mixture of paraformaldehyde (133 mg, 4.42 mmol, 122 μL, 10.0 equiv) and methyl alcohol (1.00 mL) was stirred at 60° C. for 1 h and then cooled to 0° C. To the mixture was added acetic acid (52.5 mg, 874 μmol, 0.05 mL, 1.98 equiv) and 2-(4-bromophenyl)pyrrolidine (100 mg, 442 μmol, 1.00 equiv). The mixture was allowed to stir for 1 h at room temperature prior to the addition of sodium cyanoborohydride (83.4 mg, 1.33 mmol, 3.00 equiv) and an additional hour of stirring. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=3/1) to afford 2-(4-bromophenyl)-1-methyl-pyrrolidine (100 mg, 413 μmol, 93.3% yield, 99.1% purity) as a white solid. LC-MS [M+1]: 240.1.

¹H NMR (400 Mhz, CDCl₃) δ=7.48-7.41 (m, 2H), 7.26-7.21 (m, 2H), 3.33-3.14 (m, 1H), 3.02 (t, J=8.4 Hz, 1H), 2.29 (q, J=9.2 Hz, 1H), 2.16 (s, 3H), 2.06-1.89 (m, 1H), 1.86-1.77 (m, 1H), 1.76-1.69 (m, 2H).

A mixture of 2-(4-bromophenyl)-1-methyl-pyrrolidine (48.0 mg, 200 μmol, 1.00 equiv), bis(pinacolato)diboron (76.1 mg, 300 μmol, 1.50 equiv), potassium acetate (58.9 mg, 600 μmol, 3.00 equiv), Pd(dppf)Cl₂ (14.6 mg, 20.0 μmol, 0.10 equiv) in dioxane (1.00 mL) was purged with nitrogen and then stirred at 90° C. for 2 h. The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=3/1) to afford 1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (23.0 mg, 73.3 μmol, 36.7% yield, 91.5% purity) as a white solid. LC-MS [M+1]: 288.0.

A twentieth exemplary Intermediate D, Intermediate D-20, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstituted aryl. A mixture of 2-(4-bromophenyl)pyrrolidine (50.0 mg, 221 μmol, 1.00 equiv), di-tert-butyl dicarbonate (57.9 mg, 265 μmol, 1.20 equiv) and dimethylaminopyridine (2.70 mg, 22.1 μmol, 0.10 equiv) in tetrahydrofuran (1.00 mL) was purged with nitrogen and then was stirred at 25° C. for 2 h. The mixture was filtered and concentrated under reduced pressure. The resultant residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=10/1) to afford tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (55.0 mg, 163 μmol, 73.6% yield, 96.5% purity) as a yellow oil. LC-MS [M-55]: 272.1.

A mixture of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (46.6 mg, 138 μmol, 1.00 equiv), bis(pinacolato)diboron (52.5 mg, 207 μmol, 1.50 equiv), potassium acetate (40.6 mg, 414 μmol, 3.00 equiv) and Pd(dppf)Cl₂ (10.1 mg, 13.8 μmol, 0.10 equiv) in dioxane (1.00 mL) was purged with nitrogen and then stirred at 90° C. for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=5/1) to afford tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-1-carboxylate (45.0 mg, 102 μmol, 74.3% yield, 85.0% purity) as a yellow solid. LC-MS [M-55]: 318.2.

¹H NMR (400 MHz, CDCl₃) δ=7.75 (br d, J=7.6 Hz, 2H), 7.17 (br d, J=7.6 Hz, 2H), 4.80 (br s, 1H), 3.63 (br s, 2H), 2.32 (br s, 1H), 1.98-1.75 (m, 3H), 1.58 (s, 9H), 1.35 (br s, 12H).

A twenty first exemplary Intermediate D, Intermediate D-21, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued heteroaryl. To a solution of a 1-(4-bromophenyl)-4-chloro-butan-1-one (1.00 g, 3.82 mmol, 1.00 equiv) in methanol (13.0 mL) was added portionwise NaBH₄ (300 mg, 7.93 mmol, 2.07 equiv) at room temperature. The mixture was allowed to stir at room temperature for 2 h and was subsequently quenched by the addition of water (10.0 mL). The mixture was diluted with dichloromethane (20 mL) and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product 1-(4-bromophenyl)-4-chloro-butan-1-ol (1.00 g, 3.79 mmol, 99.2% yield) as a light yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.49 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.71 (br t, J=6.0 Hz, 1H), 3.54 (s, 2H), 2.01-1.72 (m, 4H).

A solution of 1-(4-bromophenyl)-4-chloro-butan-1-ol (500 mg, 1.90 mmol, 1.00 equiv) and t-BuOK (1.0 M in THF, 1.90 mL, 1.00 equiv) was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with ether (2×20.0 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 2-(4-bromophenyl)tetrahydrofuran (420 mg, 1.85 mmol, 97.5% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=7.49-7.42 (m, 2H), 7.24-7.18 (m, 2H), 4.85 (t, J=7.2 Hz, 1H), 4.13-4.05 (m, 1H), 3.97-3.90 (m, 1H), 2.38-2.27 (m, 1H), 2.06-1.95 (m, 2H), 1.80-1.70 (m, 1H).

To a mixture of 2-(4-bromophenyl)tetrahydrofuran (150 mg, 661 μmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (252 mg, 992 μmol, 1.50 equiv), potassium acetate (195 mg, 1.99 mmol, 3.01 equiv) in dioxane (5.00 mL) was added Pd(dppf)Cl₂ (48.3 mg, 66.0 μmol, 0.10 equiv). The mixture was stirred at 105° C. for 1 h, cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated to give a residue that was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=2/1) to afford 4,4,5,5-tetramethyl-2-(4-tetrahydrofuran-2-ylphenyl)-1,3,2-dioxaborolane (240 mg, 639 μmol, 96.8% yield, 73% purity) as a colorless oil. LCMS [M+1]: 275.1.

1H NMR (400 MHz, CDCl₃) δ=7.78 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.6 Hz, 2H), 4.92 (t, J=7.2 Hz, 1H), 4.17-4.06 (m, 1H), 4.00-3.90 (m, 1H), 2.41-2.27 (m, 1H), 2.09-1.91 (m, 2H), 1.85-1.73 (m, 1H), 1.35 (s, 12H).

A twenty second exemplary Intermediate D, Intermediate D-22, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued aryl. To a cooled solution of 2-(4-bromophenyl)ethanamine (200 mg, 1.0 mmol, 155 μL, 1.00 equiv) in formalin (300 mg, 9.99 mmol, 275 μL, 10.0 equiv) was added HCOOH (5.00 mL) and the solution was stirred at 110° C. for 16 h under nitrogen. The reaction mixture was concentrated to give a residue. To the residue was added HCl (3 N, 1.00 mL) and the mixture was washed with ethyl acetate (310 mL). The aqueous phase was basified to pH=14 with NaOH (10 N, 1.00 mL) and then extracted with ethyl acetate (3×15.0 mL). The combined organic phase was washed with brine (2×15.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 2-(4-bromophenyl)-N,N-dimethyl-ethanamine (200 mg, 877 μmol, 87.7% yield) as a colorless oil.

1H NMR (400 MHz, CDCl₃) δ=7.40 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 2.73 (d, J=8.4 Hz, 2H), 2.56-2.48 (m, 2H), 2.29 (s, 6H).

A mixture of 2-(4-bromophenyl)-N,N-dimethyl-ethanamine (160 mg, 701 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (268 mg, 1.06 mmol, 1.50 equiv), Pd(dppf)Cl₂ (51.2 mg, 70.0 μmol, 0.10 equiv), potassium acetate (206 mg, 2.10 mmol, 3.00 equiv) in dioxane (8.00 mL) was purged with nitrogen and was stirred at 100° C. for 1 h. The mixture was concentrated to give a residue that was purified by prep-TLC (SiO₂, dichloromethane/methanol=10/1) to afford N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanamine (350 mg, crude) as a black oil. LCMS [M+1]: 276.2.

A twenty third exemplary Intermediate D, Intermediate D-23, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued aryl. To a solution of 1-bromo-4-iodo-benzene (200 mg, 707 μmol, 1.00 equiv), diethyl phosphite (97.6 mg, 707 μmol, 91.2 μL, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added Pd(OAc)₂ (4.76 mg, 21.2 μmol, 0.03 equiv), potassium acetate (9.02 mg, 91.9 μmol, 0.13 equiv), DPPF (23.5 mg, 42.4 μmol, 0.06 equiv) and triethylamine (107 mg, 1.06 mmol, 147 μL, 1.50 equiv). The vessel was flushed with nitrogen and stirred at 68° C. for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to afford 1-bromo-4-diethoxyphosphoryl -benzene (110 mg, 341 μmol, 48.2% yield, 90.8% purity) as a red solid. LCMS [M+3]: 294.9.

¹H NMR (400 MHz, CDCl₃) δ=7.73-7.57 (m, 4H), 4.22-3.99 (m, 4H), 1.32 (t, J=7.2 Hz, 6H).

To a solution of 1-bromo-4-diethoxyphosphoryl-benzene (100 mg, 341 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (104 mg, 409 μmol, 1.20 equiv) in dioxane (2.00 mL) was added Pd(dppf)Cl₂ (24.9 mg, 34.1 μmol, 0.10 equiv) and potassium acetate (67.0 mg, 682 μmol, 2.00 equiv) under a nitrogen atmosphere. The mixture was stirred at 100° C. for 2 h and was subsequently concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to afford 2-(4-diethoxyphosphorylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (55.0 mg, 162 μmol, 47.4% yield) as a red oil.

¹H NMR (400 MHz, CDCl₃) δ=7.93-7.87 (m, 2H), 7.85-7.76 (m, 2H), 4.21-4.01 (m, 4H), 1.36 (s, 12H), 1.32 (t, J=7.2 Hz, 6H).

A twenty fourth exemplary Intermediate D, Intermediate D-24, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued aryl. To a solution of 2-(4-bromo-3-methyl-phenyl)pyrrolidine (500 mg, 2.08 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added Boc₂O (1.05 g, 4.79 mmol, 1.10 mL, 2.30 equiv) and dimethylaminopyridine (25.4 mg, 208 μmol, 0.10 equiv). The mixture was stirred at 25° C. for 1 h and was subsequently filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=30/1 to 20/1) to afford tert-butyl 2-(4-bromo-3-methyl-phenyl)pyrrolidine-1-carboxylate (600 mg, 84.7% yield) as a yellow oil.

¹H NMR (400 MHz, CD₃OD) δ=7.46 (br d, J=8.4 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 6.92 (dd, J=1.6, 8.0 Hz, 1H), 4.73 (br s, 1H), 3.65-3.51 (m, 2H), 2.37 (s, 3H), 2.34-2.27 (m, 1H), 1.93-1.82 (m, 2H), 1.82-1.73 (m, 1H), 1.45 (br s, 3H), 1.24-1.13 (m, 6H).

A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (268 mg, 1.06 mmol, 1.20 equiv), tert-butyl 2-(4-bromo-3-methyl-phenyl) pyrrolidine-1-carboxylate (300 mg, 882 μmol, 1.00 equiv), Pd(dppf)Cl₂ (64.1 mg, 88.2 μmol, 0.10 equiv) and potassium acetate (173 mg, 1.76 mmol, 2.00 equiv) in dioxane (3.00 mL) was purged with nitrogen and then the mixture was stirred at 100° C. for 1.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=20/1 to 10/1) to afford tert-butyl 2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-1-carboxylate (260 mg, 76.1% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=7.68 (br d, J=7.6 Hz, 1H), 7.0-6.94 (m, 2H), 4.98-4.66 (m, 1H), 3.61 (br s, 2H), 2.52 (s, 3H), 2.36 (br s, 1H), 1.93-1.76 (m, 3H), 1.35 (br s, 12H), 1.29-1.25 (m 3H), 1.21 (br s, 6H).

A twenty fifth exemplary Intermediate D, Intermediate D-25, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued aryl. To a solution of 4-bromo-3-methyl-benzaldehyde (2.00 g, 10.1 mmol, 1.00 equiv) in toluene (100 mL) was added TsOH—H₂O (191 mg, 1.00 mmol, 0.10 equiv) and ethylene glycol (1.25 g, 20.1 mmol, 1.12 mL, 2.00 equiv). The mixture was stirred at 130° C. for 12 h prior to cooling to room temperature. The pH was adjusted to 9 with DMAP and then concentrated in vacuo. The residue was purified by column chromatography (neutral Al₂O₃, petroleum ether/ethyl acetate=1/0 to 100/1) to afford 2-(4-bromo-3-methyl-phenyl)-1,3-dioxolane (2.30 g, 9.46 mmol, 94.2% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.54 (d, J=8.4 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.17 (dd, J=2.4, 8.0 Hz, 1H), 5.76 (s, 1H), 4.15-4.08 (m, 2H), 4.08-4.00 (m, 2H), 2.42 (s, 3H).

A mixture of 2-(4-bromo-3-methyl-phenyl)-1,3-dioxolane (2.50 g, 10.3 mmol, 1.00 equiv), Pin₂B₂ (3.39 g, 13.4 mmol, 1.30 equiv), KOAc (2.02 g, 20.6 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (376 mg, 514 μmol, 0.05 equiv) in dioxane (30.0 mL) was purged with N₂ and then stirred at 100° C. for 6 h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (neutral Al₂O₃, petroleum ether/ethyl acetate=1/0 to 50/1) to afford 2-[4-(1,3-dioxolan-2-yl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.60 g, 8.96 mmol, 87.1% yield) as a green oil.

¹H NMR (400 MHz, CDCl₃) δ=7.78 (d, J=7.6 Hz, 1H), 7.29-7.25 (m, 2H), 5.81 (s, 1H), 4.15-4.08 (m, 2H), 4.07-4.01 (m, 2H), 2.56 (s, 3H), 1.35 (s, 12H).

A twenty sixth exemplary Intermediate D, Intermediate D-26, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued heteroaryl. A mixture of tert-butyl N-[(5-bromopyrimidin-2-yl)methyl]carbamate (100 mg, 347 μmol, 1.00 equiv), Pin₂B₂ (176 mg, 694 μmol, 2.00 equiv), KOAc (68.1 mg, 694 μmol, 2.00 equiv) and Pd(dppf)Cl₂ (25.4 mg, 34.7 μmol, 0.10 equiv) in dioxane (2.00 mL) was purged with N₂ and then stirred at 100° C. for 2 h. The reaction mixture was filtered and concentrated in vacuo to afford [2-[(tert-butoxycarbonylamino)methyl]pyrimidin-5-yl]boronic acid (100 mg, crude) as a red oil. LCMS [M-55]: 198.1.

A twenty seventh exemplary Intermediate D, Intermediate D-27, may be used to synthesize compounds of formula I, wherein R¹ a monosubstitued bicyclic heteroaryl. A mixture of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 664 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (253 mg, 996 μmol, 1.50 equiv), Pd(dppf)Cl₂ (48.55 mg, 66.35 μmol, 0.10 equiv), potassium acetate (195 mg, 1.99 mmol, 3.00 equiv) in dioxane (5.00 mL) was purged with nitrogen and then stirred at 95° C. for 2 h. The reaction mixture was cooled and filtered through a pad of Celite and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=3/1 to 1/1) to afford 6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one (180 mg, 659 μmol, 99.32% yield) as an off-white solid. LCMS [M+1]: 274.1.

1H NMR (400 MHz, CDCl₃) δ=8.07 (d, J=8.0 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.67 (s, 1H), 6.04 (s, 1H), 3.57 (dt, J=2.8, 6.4 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 1.37 (s, 12H).

A twenty eighth exemplary Intermediate D, Intermediate D-28, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued bicyclic heteroaryl. To a suspension of NaH (79.1 mg, 60%, 1.98 mmol, 2.00 equiv) in DMF (3.00 mL) at 0° C. was added dropwise a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one (270 mg, 989 μmol, 1.00 equiv) in DMF. The mixture was stirred at this temperature for an additional 30 min prior to the dropwise addition of CH₃I (1.40 g, 9.89 mmol, 615 μL, 10.0 equiv) at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched upon the addition of 20.0 mL of water followed by extraction with diethyl ether (3×30.0 mL). The combined organic layer was washed with water (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin -1-one (300 mg, crude) as a black oil. LCMS [M+1]: 288.1.

¹H NMR (400 MHz, CHCl₃-d) δ=8.07 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.63 (s, 1H), 3.56 (t, J=6.8 Hz, 2H), 3.16 (s, 3H), 3.01 (t, J=6.8 Hz, 2H), 1.36 (s, 12H).

A twenty ninth exemplary Intermediate D, Intermediate D-29, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued aryl. A mixture of 5-bromo-2-(bromomethyl)benzonitrile (100 mg, 364 μmol, 1.00 equiv), diisopropylethylamine (141 mg, 1.09 mmol, 190 μL, 3.00 equiv) and dimethylamine (2.00 M, 1.82 mL, 10.0 equiv) in dimethyl formamide (2.00 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water 5.00 mL and extracted with ethyl acetate (5.00 mL×3). The combined organic layer was washed with brine (3.00 mL×3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=3/1) to afford 5-bromo-2-[(dimethylamino)methyl]benzonitrile (50.0 mg, 209 μmol, 57.5% yield) as a yellow oil. LC-MS [M+1]: 239.2.

1H NMR (400 MHz, CDCl₃) δ=7.77 (d, J=2.0 Hz, 1H), 7.69 (dd, J=2.0, 8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 3.59 (s, 2H), 1.59 (br s, 6H).

A mixture of 5-bromo-2-[(dimethylamino)methyl]benzonitrile (30.0 mg, 125 μmol, 1.00 equiv), bis(pinacolato)diboron (63.7 mg, 251 μmol, 2.00 equiv), potassium acetate (36.9 mg, 376 μmol, 3.00 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (3.07 mg, 3.76 μmol, 0.03 equiv) in dioxane (1.00 mL) was purged with nitrogen and then stirred at 90° C. for 4 h. The mixture was filtered and concentrated under reduced pressure to give the crude product 2-[(dimethylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (40.0 mg) as a black oil which was used in the next step without further purification.

A thirtieth exemplary Intermediate D, Intermediate D-30, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued heteroaryl. To a solution of Ir(COD)₂(OMe)₂ (5.00 mg, 7.54 μmol, 0.02 equiv) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (68.5 mg, 535 μmol, 77.7 μL, 1.50 equiv) in n-pentane (0.50 mL) was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (5.00 mg, 18.6 μmol, 0.05 equiv) and the mixture was stirred at 25° C. for 20 minutes. To this mixture was added a solution of methyl 1-methylpyrazole-3-carboxylate (50.0 mg, 357 μmol, 1.00 equiv) in n-pentane (0.50 mL) and THF (0.50 mL) and the mixture was stirred at 25° C. for 24 h. The mixture was partitioned between ethyl acetate (10.0 mL) and water (10.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to afford the crude product methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate (50.0 mg, 113 μmol, 31.6% yield, 60.0% purity) as a black oil.

¹H NMR (400 MHz, CDCl₃) δ=7.28 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H), 1.35 (s, 12H).

A thirty first exemplary Intermediate D, Intermediate D-31, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued aryl, in which one substituent has two hydrogens replaced with deuteriums. To a solution of 4-bromo-N,N,3-trimethyl-benzamide (500 mg, 2.07 mmol, 1.00 equiv) in THF (5.00 mL) was added lithium tetradeuterioalumanide (235 mg, 6.20 mmol, 3.00 equiv). The mixture was stirred at 0° C. for 1.5 h and subsequently was warmed to room temperature and allowed to stir for another hour. The reaction mixture was cooled to 0° C. and diluted with THF (10.0 mL). The reaction was quenched upon the dropwise addition of deuterium oxide (0.24 mL), 15% NaOD solution in deuterium oxide (0.24 mL) at 0° C., and finally deuterium oxide (0.72 mL). The mixture was stirred at room temperature for 10 min, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, dichloromethane/methanol=50/1 to 20/1) to afford 1-(4-bromo-3-methyl-phenyl)-1,1-dideuterio-N,N-dimethyl-methanamine (220 mg, crude) as a brown oil. LCMS [M+1]: 232.1.

A thirty second exemplary Intermediate D, Intermediate D-32, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued aryl. To a solution of 4-bromo-3-methyl-aniline (4.00 g, 21.5 mmol, 1.00 equiv) in concentrated sulfuric acid (40.0 mL) and water (40.0 mL) was added sodium nitrite (1.62 g, 23.4 mmol, 1.09 equiv) at 0° C. and the mixture was stirred for 90 min. Subsequently, potassium thiocyanate (2.82 g, 29.0 mmol, 2.82 mL, 1.35 equiv) in water (16.0 mL) and thiocyanatocopper (6.80 g, 55.9 mmol, 2.60 equiv) was then added to the suspension at 5° C. After stirring at 5° C. for 2 h, the mixture was allowed to stir at room temperature for 10 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether) to afford (4-bromo-3-methyl-phenyl) thiocyanate (2.00 g, 8.77 mmol, 40.8% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=7.52 (d, J=8.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.14 (dd, J=2.4, 8.4 Hz, 1H), 2.36 (s, 3H).

A mixture of (4-bromo-3-methyl-phenyl) thiocyanate (500 mg, 2.19 mmol, 1.00 equiv), trimethyl(trifluoromethyl)silane (1.00 g, 7.04 mmol, 3.21 equiv) and tetrabutylammonium fluoride (1.00 M, 701 μL, 0.32 equiv) in tetrahydrofuran (1.00 mL) was stirred at room temperature for 4 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether) to afford 1-bromo-2-methyl-4-(trifluoromethylsulfanyl)benzene (450 mg, 1.66 mmol, 75.7% yield) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=7.59 (d, J=8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.34 (dd, J=2.4, 8.0 Hz, 1H), 2.44 (s, 3H).

A mixture of 1-bromo-2-methyl-4-(trifluoromethylsulfanyl)benzene (450 mg, 1.66 mmol, 1.00 equiv) and m-chloroperbenzoic acid (2.02 g, 85.0%, 9.96 mmol, 6.00 equiv) in chloroform (10.0 mL) was stirred at room temperature for 2 h. The mixture was heated to 60° C. and allowed to stir for an additional 10 h. The mixture was diluted with saturated sodium bicarbonate (15.0 mL) and extracted with dichloromethane (5.00 mL×3). The combined organic phase was washed with sodium sulfite (5.00 mL), brine (5.00 mL), dried over sodium sulfate, filtered and concentrated under pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether) to afford 1-bromo-2-methyl-4-(trifluoromethylsulfonyl) benzene (400 mg, 1.32 mmol, 79.5% yield) as a white solid.

1H NMR (400 MHz, CDCl₃) δ=7.88 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.4 Hz 1H), 7.71 (dd, J=2.4, 8.4 Hz, 1H), 2.55 (s, 3H).

A mixture of 1-bromo-2-methyl-4-(trifluoromethylsulfonyl)benzene (100 mg, 330 μmol, 1.00 equiv), bis(pinacolato)diboron (168 mg, 660 μmol, 2.00 equiv), potassium acetate (97.1 mg, 990 μmol, 3.00 equiv) and Pd(dppf)Cl₂ (24.1 mg, 33.0 μmol, 0.10 equiv) in dioxane (2.00 mL) was purged with nitrogen and then stirred at 90° C. for 2 h. The mixture was filtered and concentrated under reduced pressure to afford 4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethylsulfonyl)phenyl]-1,3,2-dioxaborolane (200 mg, crude) as a black solid that was used into the next step without further purification.

A thirty third exemplary Intermediate D, Intermediate D-33, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued heteroaryl. To a solution of diisopropylamine (243 mg, 2.40 mmol, 339 μL, 1.30 equiv) in THF (4.00 mL) was added dropwise n-BuLi (2.50 M, 961 uL, 1.30 equiv) at −78° C. and then the reaction was stirred at −78° C. for 30 mins. 1-cyclopropylpyrazole (200 mg, 1.85 mmol, 1.00 equiv) was added and the reaction was stirred at −78° C. for 1 h. Tributyl(chloro)stannane (602 mg, 1.85 mmol, 498 uL, 1.00 equiv) was added drop-wise and the reaction was stirred at −78° C. for another 30 min. The reaction mixture was partitioned between ethyl acetate (5.00 mL) and saturated ammonium chloride (5.00 mL). The organic phase was separated, washed with brine (5.00 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tributyl-(2-cyclopropylpyrazol-3-yl)stannane (1.00 g, crude) as a colorless oil which used for the next step without further purification.

¹H NMR (400 MHz, CDCl₃) δ=7.51 (d, J=1.6 Hz, 1H), 6.32 (d, J=1.6 Hz, 1H), 3.54-3.49 (m, 1H), 1.61-1.50 (m, 6H), 1.37-1.31 (m, 6H), 1.21-1.13 (m, 6H), 0.97-0.89 (m, 13H).

A thirty fourth exemplary Intermediate D, Intermediate D-44, may be used to synthesize compounds of formula I, wherein R¹ is a disubstitued heteroaryl. To a solution of 4-chloropyridazin-3-ol (300 mg, 2.30 mmol, 1.00 equiv) and methyl iodide (3.26 g, 23.0 mmol, 1.43 mL, 10.0 equiv) in dioxane (6.00 mL) was added silver oxide (533 mg, 2.30 mmol, 1.00 equiv). The mixture was stirred at 60° C. for 5 h. The mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to afford 4-chloro-2-methyl-pyridazin-3-one (110 mg, 761 μmol, 33.1% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.87 (d, J=4.4 Hz, 1H), 7.78 (d, J=4.4 Hz, 1H), 3.72 (s, 3H).

To a solution of 4-chloro-2-methyl-pyridazin-3-one (110 mg, 761 μmol, 1.00 equiv) and hexamethylditin (998 mg, 3.04 mmol, 631 μL, 4.00 equiv) in dioxane (2.00 mL) was added Pd(PPh₃)₄ (87.93 mg, 76.09 μmol, 0.10 equiv) under nitrogen. The mixture was stirred at 110° C. for 2 h and was subsequently filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to afford 2-methyl-4-trimethylstannyl-pyridazin-3-one (130 mg, 476 μmol, 62.6% yield) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ=7.79 (d, J=3.6 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 3.73 (s, 3H), 0.32 (s, 9H).

A thirty fifth exemplary Intermediate D, Intermediate D-35, may be used to synthesize compounds of formula I, wherein R¹ is a trisubstitued heteroaryl. To a solution of 2,5-dibromo-3-fluoro-pyridine (0.50 g, 1.96 mmol, 1.00 equiv) in THF (10.0 mL) was added n-BuLi (2.50 M, 1.18 mL, 1.50 equiv) dropwise at −65° C. The mixture was stirred at −65° C. for 0.5 h followed by the addition of N-isopropylpropan-2-amine (397 mg, 3.92 mmol, 554 μL, 2.00 equiv) one portion and stirring at this temperature for an additional 30 min. To this mixture was added methyl iodide (334 mg, 2.35 mmol, 147 μL, 1.20 equiv) and the mixture was allowed to stir at −65° C. for 1 h. The reaction mixture was quenched by the addition of satd aq NH₄Cl (10.0 mL) and the resulting mixture was extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (30.0 mL×2), dried over anh sodium sulfate, filtered and concentrated under reduced pressure to give the crude residue. The residue was purified by prep-HPLC (acidic conditions) to afford 2,5-dibromo-3-fluoro-4-methyl-pyridine (300 mg, 1.12 mmol, 56.9% yield) as a yellow solid. LCMS [M+1]: 269.7.

To a solution of 2,5-dibromo-3-fluoro-4-methyl-pyridine (0.80 g, 2.97 mmol, 1.00 equiv) in THF (10.0 mL) was added n-BuLi (2.5 M, 1.19 mL, 1.00 equiv) at −65° C. and the resultant mixture was stirred for 0.5 h followed by the dropwise addition of DMF (326 mg, 4.46 mmol, 343 μL, 1.50 equiv). After an additional 30 min of stirring at −65° C. the reaction mixture was quenched with satd aq NH₄Cl (5.00 mL) and the resulting mixture was extracted with ethyl acetate (30.0 mL×2). The combined organic phase was washed with brine (30.0 mL×2), dried over anh sodium sulfate, filtered and concentrated under reduced pressure to give the crude residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 100/1) to afford 5-bromo-3-fluoro-4-methyl-pyridine-2-carbaldehyde (300 mg, 1.38 mmol, 46.3% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ=10.20 (d, J=0.8 Hz, 1H), 8.69 (s, 1H), 2.48 (d, J=2.4 Hz, 3H).

To a solution of 5-bromo-3-fluoro-4-methyl-pyridine-2-carbaldehyde (300 mg, 1.38 mmol, 1.00 equiv) in Tol. (10.0 mL) was added TsOH—H₂O (26.2 mg, 138 μmol, 0.10 equiv) and ethylene glycol (171 mg, 2.75 mmol, 14 μL, 2.00 equiv). The mixture was stirred at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure to provide a crude residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 100/1) to afford 5-bromo-2-(1,3-dioxolan-2-yl)-3-fluoro-4-methyl-pyridine (250 mg, 954 μmol, 69.3% yield) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ=8.49 (s, 1H), 6.13 (s, 1H), 4.32-4.20 (m, 2H), 4.14-4.04 (m, 2H), 2.39 (d, J=2.4 Hz, 3H).

To a solution of 5-bromo-2-(1,3-dioxolan-2-yl)-3-fluoro-4-methyl-pyridine (450 mg, 1.72 mmol, 1.00 equiv) in Et₂O (10.0 mL) was added dropwise n-BuLi (2.5 M, 756 μL, 1.10 equiv) at −70° C. The mixture was stirred for 0.5 h at −70° C. f and subsequently 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (639 mg, 3.43 mmol, 701 μL, 2.00 equiv) was added. The mixture was stirred at −70° C. for 1 h and was quenched with satd aq NH₄Cl (10 mL). The mixture was extracted with DCM (30 mL×3) and the combined organic phase was washed with brine (50.0 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude solid. The crude material was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to afford [6-(1,3-dioxolan-2-yl)-5-fluoro-4-methyl-3-pyridyl]boronic acid (220 mg, 940 μmol, 54.8% yield, 97.0% purity) as a light yellow oil. LCMS [M+1]: 228.0.

A thirty sixth exemplary Intermediate D, Intermediate D-36, may be used to synthesize compounds of formula I, wherein R¹ is a monosubstitued aryl. To a solution of 3-phenylmorpholine (500 mg, 3.06 mmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) was added triethylamine (512 μL, 3.68 mmol, 1.20 equiv) and di-tert-butyl dicarbonate (669 mg, 3.06 mmol, 704 μL, 1.00 eq.). The mixture was stirred at 20° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue (1.30 g, crude) that was used in the next step directly.

To a solution of tert-butyl 3-phenylmorpholine-4-carboxylate (580 mg, 2.20 mmol, 1.00 equiv) in dichloromethane (6.00 mL) was added phenyl-λ³-iodanediyl bis(2,2,2-trifluoroacetate) (1.04 g, 2.42 mmol, 1.10 equiv) and iodine (559 mg, 2.20 mmol, 444 uL, 1.00 equiv). The reaction mixture was stirred at 20° C. for 2 h. The mixture was diluted with sodium bicarbonate solution (20.0 mL) and extracted with dichloromethane (10.0 mL×3). The combined organic layer was washed with saturated sodium thiosulfate solution (20.0 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 10/1) to afford tert-butyl 3-(4-iodophenyl)morpholine-4-carboxylate (260 mg, 668 μmol, 30.3% yield) as a white oil.

¹H NMR (400 MHz, DMSO-d₆) δ=7.73 (br d, J=8.4 Hz, 2H), 7.16 (br d, J=8.0 Hz, 2H), 4.92 (br s, 1H), 4.20 (br d, J=12.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.76-3.65 (m, 2H), 3.50-3.40 (m, 1H), 3.04-2.93 (m, 1H), 1.39 (s, 9H).

A mixture of tert-butyl 3-(4-iodophenyl)morpholine-4-carboxylate (260 mg, 668 μmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (254 mg, 1.00 mmol, 1.50 equiv), potassium acetate (131 mg, 1.34 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (48.9 mg, 66.8 μmol, 0.10 equiv) in dioxane (2.00 mL) was purged with and subsequently stirred at 100° C. for 2 h under a nitrogen atmosphere. The mixture was filtered and concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 10/1) to afford tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-4-carboxylate (100 mg, 257 μmol, 38.5% yield) as white oil.

¹H NMR (400 MHz, DMSO-d₆) δ=7.67 (d, J=8.0 Hz, 2H), 7.37 (d, J=7.6 Hz, 2H), 4.98 (br s, 1H), 4.29-4.23 (m, 1H), 3.86-3.66 (m, 3H), 3.51-3.42 (m, 1H), 3.07-2.96 (m, 1H), 1.41-1.38 (m, 9H), 1.30 (s, 12H).

INTERMEDIATES D-37-D-44 Characterization of Intermediates D37-D44 Int. # Structure ¹H NMR D-37

¹H NMR (400 MHz, CD₃OD) δ = 10.03 (s, 1H), 8.41 (s, 1H), 8.16-8.10 (m, 2H). 5-((dimethylamino)methyl)-2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile D-38

¹H NMR (400 MHz, DMSO-d₆) δ = 7.64 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 3.92 (s, 2H), 2.11 (s, 6H), 1.29 (s, 12H), 0.88- 0.79 (m, 2H), 0.76-0.67 (m, 2H). LCMS [M + 1]: 288.2. N,N-dimethyl-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)cyclopropan-1-amine D-39

¹H NMR (400 MHz, methanol-d₄) δ = 7.84 (s, 1H), 7.68 (s, 1H), 4.16-4.04 (m, 3H), 1.31 (s, 12H), 1.16-1.12 (m, 3H). LCMS [M + 1]: 253.3. 1-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1- yl)propan-2-ol D-40

¹H NMR (400 MHz, CDCl₃) δ = 7.74 (br d, J = 7.6 Hz, 2H), 7.17 (br d, J = 7.6 Hz, 2H), 4.79 (br s, 1H), 3.63 (br s, 2H), 2.31 (br s, 1H), 1.94-1.73 (m, 3H), 1.35 (s, 12H), 1.19 (s, 9H). tert-butyl (S)-2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)pyrrolidine-1-carboxylate D-41

LCMS [M − 55]: 318.2. tert-butyl (R)-2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)pyrrolidine-1-carboxylate D-42

LCMS [M + 1]: 274.1. 1-methyl-2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl)azetidine D-43

LCMS [M + 1]: 274.1. 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)azetidin- 2-one D-44

¹H NMR (400 MHz, DMSO-d₆) δ = 7.67 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 4.98 (br s, 1H), 4.29-4.23 (m, 1H), 3.86-3.66 (m, 3H), 3.51-3.42 (m, 1H), 3.07-2.96 (m, 1H), 1.41-1.38 (m, 9H), 1.30 (s, 12H). tert-butyl 3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate

The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention.

Example 1

(8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methanol

A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (0.100 g, 230 μmol, 1.00 equiv), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (81.6 mg, 368 μmol, 1.60 equiv), sodium bicarbonate (77.2 mg, 919 μmol, 4.00 equiv), Pd(dppf)Cl₂ (16.8 mg, 23.0 μmol, 0.100 equiv) in dioxane (2.10 mL) and water (0.700 mL) was purged with nitrogen three times. Subsequently, the mixture was stirred at 105° C. for 1 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by prep-TLC (SiO₂, PE:EA=2:3) to afford ethyl 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (60.0 mg, 47.9% yield, 82.6% purity) as an orange solid. LCMS [M+1]: 450.9.

To a solution of ethyl 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (50.0 mg, 107 μmol, 1.00 eq.) in THF (2.00 mL) was added lithium aluminum hydride (8.09 mg, 213 μmol, 2.00 eq.) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with DCM (5.00 mL) and cooled to 0° C., then quenched by addition water dropwise (0.30 mL) and 10% sodium hydroxide aqueous solution (0.30 mL), followed by water (0.90 mL). The suspension was dried with anhydrous Mg₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*50 10μ; mobile phase: [phase A: water (0.05% ammonia hydroxide v/v), phase B: ACN] and lyophilization to give (8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methanol (9.37 mg, 21.2% yield, 98.3% purity) as a white solid. LCMS [M+1]: 409.4.

¹H NMR (400 MHz, DMSO-d₆) δ=8.32 (t, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 6.86 (t, J=8.8, 1H), 6.69 (dd, J=8.4, 4.4 Hz, 1H), 6.19 (s, 1H), 5.31 (t, J=5.6 Hz, 1H), 4.72 (d, J=4.8 Hz, 2H), 4.58-4.51 (m, 4H), 3.68 (s, 3H), 3.32-3.27 (m, 2H), 2.17 (s, 3H).

Example 2

(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-2-yl)methanol

A mixture of ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,2-c]pyrimidine-2-carboxylate (120 mg, 275 μmol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (100 mg, 332 μmol, 1.21 eq.), Pd(dppf)Cl₂ (20.2 mg, 27.6 μmol, 0.10 eq.) and sodium bicarbonate (69.5 mg, 827 μmol, 32.2 μL, 3.00 eq.) in dioxane (2.00 mL), water (0.20 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 95° C. for 1 hour under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), the suspension was filtered, the filter cake was collected and dried in vacuum to give ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidine-2-carboxylate (100 mg, 68.4% yield, 99.0% purity) as a white solid. LCMS [M+1]: 525.0.

To a solution of ethyl 54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidine-2-carboxylate (50.0 mg, 94.4 μmol, 1.00 eq.) in THF (2.00 mL) was added lithium aluminum hydride (7.16 mg, 188 μmol, 2.00 eq.) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched by addition water (0.01 mL) and 10% sodium hydroxide solution (0.01 mL) at 0° C., followed by water (0.03 mL), the mixture stirred at 25° C. for 10 min, then filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (2.00 mL), the suspension was filtered, the filter cake was collected and dried in vacuum to give (54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-2-yl)methanol (14.1 mg, 29.3% yield, 94.5% purity) as a white solid. LCMS [M+1]: 483.4.

1H NMR (400 MHz, DMSO-d₆) δ=8.25 (br s, 1H), 8.01 (br s, 1H), 7.86 (s, 1H), 7.78 (br d, J=8.0 Hz, 1H), 7.61-7.55 (m, 2H), 6.94 (br t, J=9.2 Hz, 1H), 6.70 (dd, J=3.6, 8.4 Hz, 1H), 5.28 (br s, 1H), 4.73 (s, 2H), 4.58-4.50 (m, 4H), 3.30-3.29 (m, 2H), 3.26 (s, 3H), 2.29 (s, 3H).

Following the teachings of the General Reaction Schemes, Examples 1 & 2, and the intermediates disclosed herein, Examples 3-6 were prepared as shown in Table 1.

TABLE 1 Characterization of EXAMPLES 3-6 Ex. # Structure Analytical Data 3

¹H NMR (400 MHz, DMSO-d₆) δ = 8.46 (dd, J = 1.6, 4.8 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.68 (dd, J = 1.6, 7.6 Hz, 1H), 7.57 (s, 1H), 7.28 (dd, J = 4.8, 7.6 Hz, 1H), 6.99-6.87 (m, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 5.25 (s, 1H), 4.71 (s, 2H), 4.58-4.50 (m, 4H), 3.34-3.28 (m, 2H), 2.37 (s, 3H). LCMS [M + 1]: 406.1. (5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)-8-(2- methylpyridin-3-yl)imidazo[1,2- c]pyrimidin-2-yl)methanol 4

¹H NMR (400 MHz, DMSO-d₆) δ = 9.03 (d, J = 1.6 Hz, 1H), 8.32-8.21 (m, 2H), 8.03 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 9.2 Hz, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 5.32 (t, J = 5.2 Hz, 1H), 4.73 (br d, J = 5.2 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.30-3.24 (m, 2H), 2.18-2.06 (m, 1H), 1.03- 0.90 (m, 4H). LCMS [M + 1]: 432.4. (8-(6-cyclopropylpyridin-3-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[1,2- c]pyrimidin-2-yl)methanol 5

¹H NMR (400 MHz, CD₃OD) δ = 7.88 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 6.86 (t, J = 9.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.65 (dd, J = 3.6, 8.4 Hz, 1H), 4.82 (s, 2H), 4.69 (s, 2H), 4.58 (t, J = 8.8 Hz, 2H), 3.96 (s, 3H), 3.40-3.35 (m, 2H), 2.33 (s, 3H). LCMS [M + 1]: 436.4. (5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)-8-(6-methoxy-2- methylpyridin-3-yl)imidazo[1,2- c]pyrimidin-2-yl)methanol 6

¹H NMR (400 MHz, DMSO-d₆) δ = 8.32 (t, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 6.93 (t, J = 9.6 Hz, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 6.41 (d, J = 1.6 Hz, 1H), 5.29 (t, J = 5.6 Hz, 1H), 4.72 (d, J = 4.8 Hz, 2H), 4.62-4.46 (m, 4H), 3.77 (s, 3H), 3.29-3.27 (m, 2H). LCMS [M + 1]: 394.9. (5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)-8-(1-methyl-1H- pyrazol-5-yl)imidazo[1,2-c]pyrimidin- 2-yl)methanol

Example 7

1-(8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethan-1-ol

To a solution of (8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methanol (120 mg, 276 μmol, 1.00 eq.) in DCM (3.00 mL) was added Dess-Martin periodinane (175 mg, 413 μmol, 127 μL, 1.50 eq.) at 0° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), the suspension was filtered, the filter cake was collected and dried in vacuum to give 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (100 mg, 83.7% yield, 93.7% purity) as a white solid. LCMS [M+1]: 407.0.

To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (30.0 mg, 69.2 μmol, 1.00 eq.) in THF (0.50 mL) was added magnesium methyl bromide (3.00 M, 73.8 μL, 3.20 eq.) at 0° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched by addition saturated ammonium chloride aqueous solution (5.00 mL), extracted with ethyl acetate (5.00 mL×3). The combined organic layers were washed with brine (10.0 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [phase A: water (0.1% TFA), phase B: ACN]) and lyophilization to give 1-(8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethan-1-ol (8.76 mg, 29.1% yield, 97.2% purity) as yellow oil. LCMS [M+1]: 423.4.

¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (br s, 1H), 8.13 (br s, 1H), 7.87 (br s, 1H), 6.94 (t, J=9.2 Hz, 1H), 6.71 (dd, J=8.4, 3.6 Hz, 1H), 6.22 (s, 1H), 4.84 (d, J=6.4 Hz, 1H), 4.73 (d, J=4.4 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.67 (s, 3H), 3.32 (t, J=8.8 Hz, 2H), 2.20 (s, 3H), 1.43 (d, J=6.4 Hz, 3H).

Example 8

(8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanol

Step A: To a solution of 1-phenylpropane-1,2-dione (1.00 g, 6.75 mmol, 909 μL, 1.00 eq.) in CHCl₃ (10.0 mL) was added Bra (1.19 g, 7.42 mmol, 383 μL, 1.10 eq.) dropwise at 75° C., the mixture was stirred at 75° C. for 4 hr. The reaction mixture was diluted with DCM 50 mL and washed with brine (30 mL×2), the separated organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 100/1) to give compound 3-bromo-1-phenylpropane-1,2-dione (1.40 g, 4.62 mmol, 68.5% yield, 75.0% purity) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=8.06-8.01 (m, 2H), 7.72-7.65 (m, 1H), 7.56-7.52 (m, 2H), 4.41 (s, 2H), 2.54 (s, 1H).

Step B: To a solution of 6-amino-5-bromopyrimidin-2(1H)-one (0.64 g, 3.30 mmol, 1.00 eq.) in AcOH (6.00 mL) was added 3-bromo-1-phenylpropane-1,2-dione (1.40 g, 4.62 mmol, 1.40 eq.), the mixture was stirred at 120° C. for 1 hr. The reaction mixture was concentrated in vacuo to remove AcOH, the residue was triturated with MTBE 50 mL and then water (60 mL×3) mL, the precipitate was filtered and evaporated to provide 2-benzoyl-8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one (180 mg, 388 μmol, 11.7% yield, 68.5% purity) as a brown solid. LCMS [M+1]: 318.2.

Step C: To a solution of 2-benzoyl-8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one (0.18 g, 388 μmol, 1.00 eq.) in POCl₃ (5.00 mL) was added DIPEA (150 mg, 1.16 mmol, 203 μL, 3.00 eq.) dropwise at 0° C., and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was concentrated in vacuo, and the residue was purified by prep-TLC (SiO₂, PE:EA=3:1) to give compound (8-bromo-5-chloroimidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanone (45.0 mg, 133 μmol, 34.2% yield, 99.2% purity) as a red solid. LCMS [M+1]: 338.0.

Step D: To a solution of (8-bromo-5-chloroimidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanone (45.0 mg, 133 μmol, 1.00 eq.) in DMF (3.00 mL) was added DIPEA (34.3 mg, 265 μmol, 46.2 μL, 2.00 eq.) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (28.01 mg, 159.16 μmol, 1.2 eq.). The mixture was stirred at 85° C. for 30 minutes, then diluted with water 20 mL and filtered. The precipitate was dried in vacuo to give compound (8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanone (55.0 mg, 118 μmol, 88.7% yield) as a yellow solid. LCMS [M+1]: 467.1.

Step E: A mixture of (8-bromo-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanone (60.0 mg, 128 μmol, 1.00 eq.), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (42.8 mg, 193 μmol, 1.5.0 eq.), NaHCO₃ (32.4 mg, 385 μmol, 15.0 μL, 3.00 eq.), Pd(dppf)Cl₂ (14.1 mg, 19.3 μmol, 0.15 eq.) in dioxane (1.50 mL) and H₂O (0.50 mL) was degassed and purged with N₂ three times, and then the mixture was stirred at 100° C. for 1 hr under N₂ atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO₂, DCM:MeOH=20:1) to give compound (8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanone (33.3 mg, 65.9 μmol, 51.3% yield, 95.3% purity) as a yellow solid. LCMS [M+1]: 483.2.

¹H NMR (400 MHz, DMSO-d₆) δ=8.91 (s, 1H), 8.65 (br s, 1H), 8.19 (d, J=7.2 Hz, 2H), 7.81 (s, 1H), 7.71-7.65 (m, 1H), 7.61-7.55 (m, 2H), 6.95 (t, J=9.6 Hz, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 6.25 (s, 1H), 4.73 (br d, J=2.8 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.76 (s, 3H), 2.18 (s, 3H).

Step F: To a solution of (8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanone (19.0 mg, 37.5 μmol, 1.00 eq.) in THF (2.00 mL) was added NaBH₄ (1.70 mg, 45.0 μmol, 1.20 eq.) at 0° C., the mixture was stirred at 10° C. for 1 hr. The reaction mixture was quenched with water (0.1 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [phase A: water (0.1% TFA), phase B: ACN]) to give compound (8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(phenyl)methanol (7.00 mg, 14.3 μmol, 38.2% yield, 99.1% purity) as a white solid. LCMS [M+1]: 485.3.

¹H NMR (400 MHz, DMSO-d₆) δ=8.52 (br s, 1H), 8.07 (s, 1H), 7.78 (br s, 1H), 7.43 (d, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 2H), 7.29-7.22 (m, 1H), 6.98-6.90 (m, 1H), 6.70 (dd, J=4.0, 8.8 Hz, 1H), 6.18 (s, 1H), 5.79 (s, 1H), 4.70 (br d, J=4.8 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.60 (s, 3H), 3.31 (br t, J=8.8 Hz, 2H), 2.18 (s, 3H).

Example 9

8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-amine

Step A: To a solution of (8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methanol (1.50 g, 3.67 mmol, 1.00 eq.) in THF (15.0 mL) was added di-tert-butyl dicarbonate (2.00 g, 9.18 mmol, 2.11 mL, 2.50 eq.) and DMAP (44.9 mg, 367 μmol, 0.10 eq.), the reaction mixture was stirred at 80° C. for 1 hour. The reaction was concentrated in vacuo to give a residue, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1 to dichloromethane/methanol=20/1) to give tert-butyl (2-(((tert-butoxycarbonyl)oxy)methyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (2.10 g, 3.45 mmol, 93.9% yield) as brown oil. LCMS [M+1]: 609.1.

Step B: To a solution of (2-(((tert-butoxycarbonyl)oxy)methyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (400 mg, 657 μmol, 1.00 eq.) in methanol (6.00 mL) was added potassium carbonate (182 mg, 1.31 mmol, 2.00 eq.), the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (dichloromethane/methanol: 10/1) to give tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(hydroxymethyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (200 mg, 393 μmol, 59.8% yield) as a white solid. LCMS [M+1]: 509.3.

Step C: To a solution of tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(hydroxymethyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (80.0 mg, 157 μmol, 1.00 eq.) in THF (4.00 mL) was added sodium hydride (12.6 mg, 315 μmol, 60.0% purity, 2.00 eq.) at 0° C., the reaction mixture was stirred at 0° C. for 30 minutes, then methyl iodide (44.7 mg, 315 μmol, 19.6 μL, 2.00 eq.) was added dropwise. The reaction mixture was then warmed to 25° C. and stirred for 30 minutes. The reaction was quenched with water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (10.0 mL×3). The combined organic phase was washed with brine (10.0 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, the residue was purified by prep-TLC (dichloromethane/methanol=10/1) to give tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (71.0 mg, 128 μmol, 81.5% yield, 94.4% purity) as brown oil. LCMS [M+1]: 523.3.

Step D: A solution of tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (71.0 mg, 128 μmol, 1.00 eq.) in TFA (0.30 mL) and DCM (1.00 mL) was stirred at 25° C. for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. (10.0 mL), extracted with DCM (5.00 mL×3). The combined organic phases were washed with brine (5.00 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was triturated with petroleum ether/ethyl acetate=1/1 (5.00 mL), filtered, the filter cake was collected and dried in vacuo to 8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-amine (15.9 mg, 35.1 μmol, 27.4% yield, 93.4% purity) as an off-white solid. LCMS [M+1]: 423.3.

¹H NMR (400 MHz, CD₃OD) δ=7.91 (s, 1H), 7.71 (s, 1H), 6.84 (t, J=9.2 Hz, 1H), 6.62 (dd, J=3.6, 8.4 Hz, 1H), 6.22 (s, 1H), 4.81 (s, 2H), 4.59-4.54 (m, 2H), 4.54 (s, 2H), 3.70 (s, 3H), 3.42 (s, 3H), 3.35 (t, J=8.8 Hz, 2H), 2.27 (s, 3H).

Example 10

2-(aminomethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazol[1,2-c]pyramidin-5-amine

Step A: A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (160 mg, 367 μmol, 1 eq.), sodium hydroxide (1 M, 1.10 mL, 3 eq.) in methanol (3.30 mL) was stirred at 55° C. for 30 minutes under N₂ atmosphere. The mixture was concentrated in vacuo to give a residue, water (1.00 mL) was added and HCl (1 M) was added until pH=2, the solid was collected through filtration, dried in vacuo to give compound 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid (124 mg, 304 μmol, 82.8% yield) as a white solid. LCMS: [M+1] 408.8.

Step B: A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid (124 mg, 304. μmol, 1.00 eq.), ammonium chloride (48.8 mg, 913 μmol, 31.9 μL, 3.00 eq.), HATU (173 mg, 456 μmol, 1.50 eq.), DIEA (314 mg, 2.44 mmol, 424 μL, 8 eq.) in DMF (1.00 mL) was degassed and purged with N₂ 3 times, and then the mixture was stirred at 30° C. for 1 hr under a N₂ atmosphere. The mixture was concentrated in vacuo to give a residue. Water (1.00 mL) was added to the residue and the solid was collected through filtration, then dried in vacuo to give compound 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxamide (100 mg, crude) as a white solid which was used into the next step without further purification.

Step C: A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxamide (100 mg, 246. μmol, 1.00 eq.), TEA (484 mg, 4.79 mmol, 666 μL, 19.4 eq.) in THF (2.00 mL) was added TFAA (302 mg, 1.44 mmol, 200 μL, 5.84 eq.) at 0° C., and then the mixture was stirred at 0-30° C. for 40 mins. under a N₂ atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate 5/1 to 0/1) to give compound 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (100 mg, 245 μmol, 99.7% yield, 95.3% purity) as a yellow solid. LCMS: [M+1] 387.8.

Step D: A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (90.0 mg, 231 μmol, 1.00 eq.), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103 mg, 463 μmol, 2.00 eq.), Pd(dppf)Cl₂ (16.9 mg, 23.1 μmol, 0.100 eq.), sodium bicarbonate (58.4 mg, 695 μmol, 27.0 μL, 3 eq.) in dioxane (6.00 mL) and water (3.00 mL) was degassed and purged with N₂ 3 times, and then the mixture was stirred at 100° C. for 2 hrs under a N₂ atmosphere. Water (8.00 mL) was added and the mixture was extracted with ethyl acetate (8.00 mL×3). The organic layers were concentrated in vacuo to give a residue. The residue was purified by reversed phased prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B %: 33%-63%,13 min) to give compound 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (51.0 mg, 120 μmol, 52.0% yield, 95.4% purity) as a white solid. LCMS: [M+1] 404.

¹H NMR (400 MHz, DMSO-d₆) δ=8.92 (s, 1H), 8.64 (br t, J=4.8 Hz, 1H), 7.86 (s, 1H), 6.99-6.91 (m, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.72 (br d, J=4.4 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.67 (s, 3H), 3.31 (t, J=8.8 Hz, 2H), 2.18 (s, 3H).

Step E: To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (80.0 mg, 193 μmol, 1.00 eq.) in THF (2.00 mL) and NH₃H₂O (14.0 M, 0.80 mL, 58.0 eq.) was added Raney nickel (16.53 mg, 192.95 μmol, 1.00 eq.) under nitrogen. The suspension was degassed under vacuum and purged with nitrogen several times and stirred under an H2 atmosphere (15 psi) at 25° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL×2), the suspension was filtered and the filter cake was collected, and dried in vacuo to give 2-(aminomethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (34.8 mg, 41.5% yield, 94.0% purity) as a yellow solid. LCMS: [M+1] 408.1.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (br.s, 1H), 8.21 (s, 1H), 7.97 (br.s, 2H), 7.74 (s, 1H), 6.94 (t, J=8.4 Hz, 1H), 6.74-6.66 (m, 1H), 6.21 (s, 1H), 4.72 (s, 2H), 4.55 (t, J=8.0 Hz, 2H), 4.12 (s, 2H), 3.69 (s, 3H), 3.31-3.27 (m, 2H), 2.18 (s, 3H).

Examples 11 & 12

2-(1-aminoethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine

Step A: To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (3.50 g, 9.02 mmol, 1.00 eq.) in THF (10.0 mL) was added methyl magnesium bromide (3.00 M, 18.0 mL, 6.00 eq) dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours, then the reaction was added methanol (5.00 mL), after 15 min the mixture was added sodium borohydride (1.36 g, 36.1 mmol, 4.00 eq.) and stirred at 0-25° C. for 7 hours. The reaction was poured into ice-water (15.0 mL) and stirred for 15 mins, the aqueous phase was extracted with ethyl acetate (30.0 mL×3). The combined organic phases were washed with brine (30.0 mL×3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2-(1-aminoethyl)-8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (3.00 g, crude) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.28 (t, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 6.95-6.88 (m, 1H), 6.68 (dd, J=4.0, 8.8 Hz, 1H), 5.62 (br s, 1H), 5.43-5.33 (m, 1H), 4.65 (d, J=4.8 Hz, 2H), 4.53 (t, J=8.8 Hz, 2H), 3.88-3.75 (m, 1H), 3.25 (t, J=8.8 Hz, 2H), 1.50 (d, J=6.8 Hz, 3H).

Step B: To a solution of 2-(1-aminoethyl)-8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (3.00 g, 7.38 mmol, 1.00 eq.) and di-tert-butyl dicarbonate (3.22 g, 14.8 mmol, 3.39 mL, 2.00 eq.) in THF (15.0 mL) was added TEA (2.24 g, 22.15 mmol, 3.08 mL, 3.00 eq.) and DMAP (90.2 mg, 738 μmol, 0.10 eq.). The mixture was stirred at 40° C. for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 2/1) to give tert-butyl (1-(8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (1.30 g, 2.57 mmol, 34.8% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.28 (br t, J=4.8 Hz, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.25 (br d, J=8.0 Hz, 1H), 6.96-6.86 (m, 1H), 6.68 (dd, J=4.0, 8.8 Hz, 1H), 4.78-4.69 (m, 1H), 4.65 (t, J=4.0 Hz, 2H), 4.53 (t, J=8.8 Hz, 2H), 3.25 (t, J=8.4 Hz, 2H), 1.43-4.35 (m, 12H).

Step C: To a solution of tert-butyl (1-(8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (600 mg, 1.18 mmol, 1.00 eq.) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (395 mg, 1.78 mmol, 1.50 eq.) in dioxane (1.00 mL) and water (0.20 mL) was added sodium bicarbonate (199 mg, 2.37 mmol, 92.2 μL, 2.00 eq.) and Pd(dppf)Cl₂ (86.7 mg, 118 μmol, 0.10 eq.) under nitrogen atmosphere. The mixture was stirred at 100° C. for 1 hour under a nitrogen atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 1/1) to give tert-butyl (1-(8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (500 mg, 767 μmol, 64.7% yield, 80.0% purity) as a red solid. LCMS [M-99]: 422.3.

Step D: To a solution of tert-butyl (1-(8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (500 mg, 767 μmol, 1.00 eq.) in dichloromethane (6.00 mL) was added TFA (2.00 mL). The mixture was stirred at 25° C. for 30 minutes. The mixture was adjusted to pH=8 with ammonium hydroxide and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: waters xbridge C18 150×50 mm x 10 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 22%-52%,11.5 min) to give 2-(1-aminoethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (280 mg, 661 μmol, 86.2% yield, 99.5% purity) as a white solid. LCMS [M+1]: 422.3.

¹H NMR (400 MHz, DMSO-d₆) δ=8.23 (br t, J=4.8 Hz, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 6.96-6.88 (m, 1H), 6.68 (dd, J=3.6, 8.4 Hz, 1H), 6.17 (s, 1H), 4.69 (br d, J=4.0 Hz, 2H), 4.53 (t, J=8.8 Hz, 2H), 4.04-3.99 (m, 1H), 3.68 (s, 3H), 3.29-3.26 (m, 2H), 2.16 (s, 3H), 1.99 (br s, 2H), 1.32 (d, J=6.4 Hz, 3H).

Enantiomers of 2-(1-aminoethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine were separated by chiral SFC to provide enantiomerically pure compounds, Example 11 and Example 12.

Example 11: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 μm; Mobile phase: Phase A for CO₂, and Phase B for IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO₂ from 5% to 40%. Flow rate: 3 mL/min; Wavelength: 220 nm. Column Temp: 35° C.; Back Pressure: 100 Bar. t_(r)=1.742 min. LCMS [M+1]: 422.1.

¹H NMR (400 MHz, CD₃OD) δ=8.23 (s, 1H), 8.07 (s, 1H), 6.90-6.79 (m, 1H), 6.72 (s, 1H), 6.64 (dd, J=3.9, 8.7 Hz, 1H), 4.88-4.86 (m, 2H), 4.69 (q, J=6.8 Hz, 1H), 4.59 (t, J=8.7 Hz, 2H), 3.98 (s, 3H), 3.41 (t, J=8.6 Hz, 2H), 2.47 (s, 3H), 1.73 (d, J=6.8 Hz, 3H).

Example 12: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 μm; Mobile phase: Phase A for CO₂, and Phase B for IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO₂ from 5% to 40%. Flow rate: 3 mL/min; Wavelength: 220 nm. Column Temp: 35° C.; Back Pressure: 100 Bar. t_(r)=1.796 min. LCMS [M+1]: 422.3.

¹H NMR (400 MHz, CD₃OD) δ=8.27-8.16 (m, 1H), 8.10-7.99 (m, 1H), 6.94-6.81 (m, 1H), 6.74-6.60 (m, 2H), 4.94-4.89 (m, 2H), 4.69 (br t, J=6.8 Hz, 1H), 4.60 (t, J=8.8 Hz, 2H), 3.96 (m, 3H), 3.42 (t, J=8.8 Hz, 2H), 2.46 (br d, J=10.0 Hz, 3H), 1.80-1.71 (m, 3H).

Example 13

2-(aminomethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-5-amine

Step A: To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (121 mg, 302. μmol, 1.00 eq) and 4,4,5,5-tetramethyl-2-(2-methyl-4-(methyl sulfonyl)phenyl)-1,3,2-dioxaborolane (150 mg, 456 μmol, 1.50 eq), sodium bicarbonate (76.0 mg, 905 μmol, 35.2μL, 3.00 eq) in a mixture solvent of dioxane (1.70 mL) and water (0.30 mL) was added Pd(dppf)Cl₂.CH₂Cl₂ (25.0 mg, 30.6 μmol, 0.10 eq). The mixture was stirred at 95° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was evaporated to give a residue, the residue was purified by prep-TLC (SiO₂, dichloromethane:methanol=20:1) to give 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methyl sulfonyl)phenyl)imidazo[1,2-c]pyrimidine-2-carbonitrile (80.0 mg, 49.4% yield, 89.0% purity) as a light yellow solid. LCMS [M+1]: 478.1.

¹H NMR (400 MHz, DMSO-d₆) δ=8.93 (s, 1H), 8.58 (t, J=5.2 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.83-7.78 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.04-6.89 (m, 1H), 6.72 (dd, J=3.6, 8.4 Hz, 1H), 4.73 (d, J=4.8 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.37-3.29 (m, 2H), 3.26 (s, 3H), 2.28 (s, 3H).

Step B: A mixture of 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidine-2-carbonitrile (80.0 mg, 149 μmol, 1.00 eq) and Raney nickel (15.0 mg) in methanol (1.50 mL) and ammonium hydroxide (0.50 mL) was degassed and purged with H₂ 3 times, and then the mixture was stirred under H2 (15 psi) at 25° C. for 12 hours. The reaction mixture was filtered and the filtrate was evaporated to give a residue, the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%, 10 min) to give 2-(aminomethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-5-amine (29.1 mg, 37.5% yield, 99.4% purity, HCl salt) as a white solid. LCMS [M+1]: 482.2.

¹H NMR (400 MHz, DMSO-d₆) δ=8.82 (s, 1H), 8.43 (s, 3H), 8.35 (s, 1H), 7.90 (s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.75 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 6.94 (t, J=9.2 Hz, 1H), 6.70 (dd, J=3.6, 8.4 Hz, 1H), 4.74 (br d, J=4.8 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 4.10 (br d, J=5.6 Hz, 2H), 3.34 (t, J=8.8 Hz, 2H), 3.27 (s, 3H), 2.30 (s, 3H).

Following the teachings of the General Reaction Schemes, Examples 10-13, and the intermediates disclosed herein, Examples 14-24 were prepared as shown in Table 2.

TABLE 2 Characterization of EXAMPLES 14-24 Ex. # Structure Analytical Data 14

¹H NMR (400 MHz, DMSO-d₆) δ = 8.52 (t, J = 5.2 Hz, 1H), 8.29 (br s, 3H), 8.19 (s, 1H), 8.13 (s, 1H), 8.09-8.04 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.20-7.13 (m, 1H), 6.97-6.90 (m, 1H), 6.70 (dd, J = 3.6, 8.4 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.20 (br d, J = 5.6 Hz, 2H), 3.31 (t, J = 8.4 Hz, 2H). LCMS [M + 1]: 408.2. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(3- fluorophenyl)imidazo[1,2-c]pyrimidin- 5-amine 15

¹H NMR (400 MHz, DMSO-d₆) δ = 8.66 (s, 1H), 8.19 (s, 4H), 7.89 (s, 1H), 6.98-6.90 (m, 2H), 6.71 (dd, J = 3.6, 8.8 Hz, 1H), 4.75 (br d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.16 (br d, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.30-3.28 (m, 2H). LCMS [M + 1]: 462.3. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(1- methyl-3-(trifluoromethyl)-1H-pyrazol- 5-yl)imidazo[1,2-c]pyrimidin-5-amine 16

¹H NMR (400 MHz, DMSO-d₆) δ = 8.60 (t, J = 4.8 Hz, 1H), 8.29 (br s, 3H), 8.25 (s, 1H), 8.20 (s, 1H), 8.00 (dd, J = 2.0, 9.6 Hz, 2H), 7.20-7.14 (m, 1H), 6.97-6.89 (m, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.21 (br d, J = 6.0 Hz, 2H), 3.31 (t, J = 8.8 Hz, 2H). LCMS [M + 1]: 426.0. 2-(aminomethyl)-8-(3,5- difluorophenyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4- yl)methyl)imidazo[1,2-c]pyrimidin- 5-amine 17

¹H NMR (400 MHz, DMSO-d₆) δ = 8.39 (br d, J = 4.8 Hz, 1H), 8.16 (br s, 3H), 7.63 (s, 1H), 7.33- 7.26 (m, 1H), 7.24-7.12 (m, 2H), 6.98-6.92 (m, 1H), 6.71 (dd, J = 3.6, 8.4 Hz, 1H), 4.73 (br d, J = 4.8 Hz, 2H), 4.56 (t J = 8.4 Hz, 2H), 4.13- 4.09 (m, 2H), 3.33 (br t, J = 8.8 Hz, 2H), 2.08 (d, J = 2.0 Hz, 3H). LCMS [M + 1]: 422.0. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(3- fluoro-2-methylphenyl)imidazo[1,2- c]pyrimidin-5-amine 18

¹H NMR (400 MHz, DMSO-d₆) δ = 8.63-8.53 (m, 1H), 8.37-8.13 (m, 4H), 7.77 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 6.93 (t, J = 9.6 Hz, 1H), 6.70 (dd, J = 3.6, 8.4 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 4.73 (br d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.4 Hz, 2H), 4.14 (br s, 2H), 3.79 (s, 3H), 3.32-3.28 (m, 2H). LCMS [M + 1]: 394.1. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(1- methyl-1H-pyrazol-5-yl)imidazo[1,2- c]pyrimidin-5-amine 19

¹H NMR (400 MHz, DMSO-d₆) δ = 8.68 (d, J = 4.8 Hz, 1H), 8.61-8.52 (m, 1H), 8.19 (s, 5H), 7.77 (s, 1H), 7.67 (br t, J = 6.0 Hz, 1H), 6.93 (t, J = 8.8 Hz, 1H), 6.70 (dd, J = 4.0, 8.4 Hz, 1H), 4.74 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.11 (br d, J = 5.6 Hz, 2H), 3.32 (t, J = 8.8 Hz, 2H), 2.53 (s, 3H). LCMS [M + 1]: 405.2. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(2- methylpyridin-3-yl)imidazo[1,2- c]pyrimidin-5-amine 20

¹H NMR (400 MHz, DMSO-d₆) δ = 8.44-8.34 (m, 1H), 8.28-8.14 (m, 4H), 7.67-7.59 (m, 2H), 6.94 (t, J = 8.8 Hz 1H), 6.75-6.67 (m, 2H), 4.73 (br d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.15-4.08 (m, 2H), 3.89 (s, 3H), 3.32 (t, J = 8.8 Hz, 2H), 2.31 (s, 3H). LCMS [M + 1]: 435.3. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(6- methoxy-2-methylpyridin-3- yl)imidazo[1,2-c]pyrimidin-5-amine 21

¹H NMR (400 MHz, DMSO-d₆) δ = 8.37 (br t, J = 5.2 Hz, 1H), 8.22 (br s, 3H), 8.16 (s, 1H), 7.96 (s, 1H), 7.87-7.78 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.97-6.89 (m, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 4.74 (d, J = 5.2 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.19 (br d, J = 5.6 Hz, 2H), 3.32 (br t, J = 8.8 Hz, 2H), 2.38 (s, 3H). LCMS [M + 1]: 404.1. 2-(aminomethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(m- tolyl)imidazo[1,2-c]pyrimidin-5-amine 22

¹H NMR (400 MHz, DMSO-d₆) δ = 8.44 (br t, J = 4.8 Hz, 1H), 8.16 (br s, 4H), 7.66 (s, 1H), 7.60- 7.55 (m, 1H), 7.54-7.49 (m, 1H), 7.47-7.37 (m, 2H), 6.94 (t, J = 9.6 Hz, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 4.73 (br d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.10 (br d, J = 5.6 Hz, 2H), 3.32 (br t, J = 8.8 Hz, 2H). LCMS [M + 1]: 424.3. 2-(aminomethyl)-8-(2-chlorophenyl)-N- ((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)imidazo[1,2-c]pyrimidin- 5-amine 23

¹H NMR (400 MHz, CD₃OD) δ = 8.03 (s, 1H), 7.78 (s, 1H), 7.11-7.02 (m, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 4.79 (s, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.26 (s, 2H), 3.76 (s, 3H), 3.29-3.25 (m, 2H), 2.28 (s, 3H). LCMS [M + 1]: 390.4. 2-(aminomethyl)-N-((2,3- dihydrobenzofuran-4-yl)methyl)-8- (1,3-dimethyl-1H-pyrazol-5- yl)imidazo[1,2-c]pyrimidin-5-amine 24

¹H NMR (400 MHz, CD₃OD) δ = 8.02 (s, 1H), 7.83 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 3.2, 8.8 Hz, 1H), 7.14-7.07 (m, 2H), 6.29 (s, 1H), 5.12 (d, J = 0.8 Hz, 2H), 4.23 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H). LCMS [M + 1]: 406.3. 2-(aminomethyl)-8-(1,3-dimethyl-1H- pyrazol-5-yl)-N-((5-fluorobenzofuran- 4-yl)methypimidazo[1,2-c]pyrimidin- 5-amine

Example 25

8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-((methylamino)methyl)imidazo[1,2-c]pyrimidin-5-amine

To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (30.0 mg, 69.2 μmol, 1.00 eq.), methylamine (2.00 M in THF, 69.1 μL, 2.00 eq.) in methanol (2.00 mL) was added acetic acid (2.08 mg, 34.7 μmol, 1.98 μL, 0.50 eq.). The reaction mixture was stirred at 40° C. for 2 hours, then the mixture was added sodium triacetoxyborohydride (44.0 mg, 207 μmol, 3.00 eq.) in one portion and stirred at 40° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), the suspension was filtered, the filter cake was washed with water (2.00 mL), collected and dried in vacuo to 8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-((methylamino)methyl)imidazo[1,2-c]pyrimidin-5-amine (8.07 mg, 27.1% yield, 97.7% purity) as a white solid. LCMS [M+1]: 422.4.

¹H NMR (400 MHz, DMSO-d₆) δ=8.40 (br s, 1H), 8.10 (s, 1H), 7.71 (s, 1H), 6.94 (br t, J=9.6 Hz, 1H), 6.77-6.63 (m, 1H), 6.20 (s, 1H), 4.72 (br d, J=4.4 Hz, 2H), 4.55 (br t, J=8.8 Hz, 2H), 3.98 (s, 2H), 3.69 (s, 3H), 3.30-3.28 (m, 2H), 2.46 (br s, 3H), 2.18 (s, 3H).

Example 26

8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-((dimethylamino)methyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine

To a solution of 2-(aminomethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (19.9 mg, 45.8 μmol, 1.00 eq.) in methanol (1.00 mL) and DCE (1.00 mL) was added formaldehyde (7.44 mg, 91.6 μmol, 6.82 μL, 37.0% purity, 2.00 eq.), formic acid (220 μg, 4.58 μmol, 0.10 eq.) and sodium triacetoxyborohydride (19.4 mg, 91.6 μmol, 2.00 eq.), the reaction mixture was stirred at 25° C. for 12 hours. The reaction was filtered and concentrated in vacuo to give a residue, the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150×25×10 μm; mobile phase: [water (0.1% TFA)-ACN]; B %: 20%-50%,9 min) and lyophilization to give 2-[(dimethylamino)methyl]-8-(2,5-dimethylpyrazol-3-yl)-N-[(5-fluoro -2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,2-c]pyrimidin-5-amine (7.82 mg, 14.1 μmol, 30.7% yield, 98.9% purity, trifluoroacetic acid salt) as a white solid. LCMS [M+1]: 436.2.

1H NMR (400 MHz, CD₃OD) δ=8.16 (s, 1H), 7.84 (s, 1H), 6.89-6.83 (m, 1H), 6.65 (dd, J=4.0, 8.8 Hz, 1H), 6.30 (s, 1H), 4.84 (s, 3H), 4.59 (t, J=8.8 Hz, 2H), 4.46 (s, 2H), 3.77 (s, 3H), 3.41 (t, J=8.4 Hz, 2H), 2.92 (s, 6H), 2.30 (s, 3H).

Example 27

2-(((8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methyl)amino)ethane-1-sulfonyl fluoride

To a solution of 2-(aminomethyl)-8-(2,5-dimethylpyrazol-3-yl)-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,2-c]pyrimidin-5-amine (20.0 mg, 49.1 μmol, 1.00 eq.) in dichloromethane (0.50 mL) was added ethenesulfonyl fluoride (2.70 mg, 24.5 μmol, 0.50 eq). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Luna C18 150×25 5u; mobile phase: [water (0.075% TFA)-ACN]; B %: 18%-48%, 9 min) to give 22-(((8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methyl)amino)ethane-1-sulfonyl fluoride (8.00 mg, 11.2 μmol, 22.9% yield, 88.6% purity) as a yellow solid. LCMS [M+1]: 518.2.

¹H NMR (400 MHz, DMSO-d₆) δ=9.53-8.86 (m, 1H), 8.57 (br t, J=5.2 Hz, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 6.97-6.89 (m, 1H), 6.70 (dd, J=4.0, 8.8 Hz, 1H), 6.21 (s, 1H), 4.72 (br d, J=4.8 Hz, 2H), 4.54 (t, J=8.8 Hz, 2H), 4.38 (s, 2H), 4.36-4.29 (m, 2H), 3.68 (s, 3H), 3.61-3.57 (m, 2H), 3.31 (br t, J=8.8 Hz, 2H), 2.17 (s, 3H).

Example 28

2,2′-(((8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methyl)azanediyl)bis(ethane-1-sulfonyl fluoride)

To a solution of 2-(aminomethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (30.0 mg, 73.6 μmol, 1 eq.) in dichloromethane (0.50 mL) was added ethenesulfonyl fluoride (7.30 mg, 66.3 μmol, 0.90 eq.). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Luna C18 150×25 5μ; mobile phase: [water (0.075% TFA)-ACN]; B %: 30%-60%, 9 min) to give 2,2′-(((8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methyl)azanediyl)bis(ethane-1-sulfonyl fluoride) (30.0 mg, 40.2 μmol, 54.6% yield, 99.3% purity, trifluoroacetic acid salt) as white oil. LCMS [M+1]: 628.4.

¹H NMR (400 MHz, DMSO-d₆) δ=8.64 (br s, 1H), 8.13 (s, 1H), 7.86 (br s, 1H), 6.99-6.91 (m, 1H), 6.70 (dd, J=4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.74 (d, J=4.8 Hz, 2H), 4.54 (t, J=8.8 Hz, 2H), 4.19-4.12 (m, 4H), 3.91 (s, 2H), 3.68 (s, 3H), 3.31 (t, J=8.8 Hz, 2H), 3.13 (t, J=6.8 Hz, 4H), 2.19 (s, 3H).

Example 29

2-(azetidin-1-ylmethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-c]pyrimidin-5-amine

To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (70.0 mg, 141 μmol, 1.00 eq.), azetidine hydrochloride (40.3 mg, 430 μmol, 3.05 eq.), Ti(Oi-Pr)₄ (119 mg, 419 μmol, 124 μL, 2.96 eq.) and acetic acid (1.05 mg, 17.5 mol, 1.00 μL, 0.12 eq.) in DCE (2.50 mL) was added sodium cyanoborohydride (17.5 mg, 278 mol, 1.97 eq.), the reaction was stirred at 25° C. for 1.5 hours. The reaction mixture diluted with ammonium chloride solution (20.0 mL) and the suspension was filtered, the filtrate was extracted with ethyl acetate (30.0 mL×2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%) to give 2-(azetidin-1-ylmethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-c]pyrimidin-5-amine (25.6 mg, 48.4 μmol, 34.3% yield, 91.5% purity, hydrochloride) as a white solid. LCMS [M+1]: 448.2.

¹H NMR (400 MHz, CD₃OD) δ=8.43 (s, 1H), 8.21 (s, 1H), 6.91-6.83 (m, 1H), 6.81 (s, 1H), 6.67 (dd, J=4.0, 8.8 Hz, 1H), 4.91 (br s, 2H), 4.66 (s, 2H), 4.61 (t, J=8.8 Hz, 2H), 4.40-4.17 (m, 4H), 4.02 (s, 3H), 3.44 (t, J=8.8 Hz, 2H), 2.68-2.41 (m, 5H).

Example 30

2-((cyclobutylamino)methyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine

To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (30.0 mg, 73.8 μmol, 1.00 eq.) and cyclobutylamine (15.8 mg, 221 μmol, 19.0 μL, 3.00 eq.) in methanol (2.00 mL) was added acetic acid (39.4 mg, 656 μmol, 37.5 μL, 8.88 eq.). The mixture was stirred at 50° C. for 2 hours then sodium cyanoborohydride (9.28 mg, 148 μmol, 2.00 eq.) was added to the reaction mixture at 20° C. The reaction mixture was stirred at 20° C. for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%) to give 2-[(cyclobutylamino)methyl]-8-(2,5-dimethylpyrazol-3-yl)-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,2-c]pyrimidin-5-amine (17.1 mg, 36.0 μmol, 48.8% yield, 96.9% purity) as a white solid. LCMS [M+1]: 462.5.

¹H NMR (400 MHz, DMSO-d₆) δ=10.00 (br s, 1H), 9.48 (br s, 1H), 8.65 (s, 1H), 7.97 (s, 1H), 6.96-6.87 (m, 1H), 6.68 (dd, J=4.0, 8.8 Hz, 1H), 6.41 (s, 1H), 4.73 (br s, 2H), 4.53 (t, J=8.4 Hz, 2H), 4.15 (br s, 2H), 4.09-3.97 (m, 1H), 3.77 (s, 3H), 3.73-3.60 (m, 1H), 3.35 (br t, J=8.8 Hz, 2H), 2.30-2.18 (m, 5H), 2.17-2.08 (m, 2H), 1.81-1.66 (m, 2H).

Following the teachings of the General Reaction Schemes, Examples 29-30, and the intermediates disclosed herein, Examples 31-33 were prepared as shown in Table 3.

TABLE 3 Characterization of EXAMPLES 31-33 Ex. # Structure Analytical Data 31

¹H NMR (400 MHz, DMSO-d₆) δ ppm = 8.24 (br s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 6.98-6.88 (m, 1H), 6.69 (dd, J = 8.4, 4.0 Hz, 1H), 6.18 (s, 1H), 5.27 (br s, 1H), 4.71 (br s, 2H), 4.54 (t, J = 8.8 Hz, 2H), 4.24-4.10 (m, 1H), 3.68 (s, 3H), 3.61 (s, 2H), 3.60-3.56 (m, 2H), 3.31-3.27 (m, 2H), 2.87-2.77 (m, 2H), 2.17 (s, 3H). LCMS [M + 1]: 464.4. 1-((8-(1,3-dimethyl-1H-pyrazol-5-yl)- 5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[1,2- c]pyrimidin-2-yl)methyl)azetidin-3-ol 32

¹H NMR (400 MHz, DMSO-d₆) δ = 8.30 (br s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.38-7.28 (m, 4H), 7.25-7.20 (m, 1H), 6.93 (t, J = 9.6 Hz, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 6.19 (s, 1H), 4.71 (br d, J = 4.0 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.76(s, 2H), 3.75 (s, 2H), 3.70-3.65 (m, 3H), 3.31-3.26 (m, 2H), 2.17 (s, 3H). LCMS [M + 1]: 498.4. 2-((benzylamino)methyl)-8-(1,3- dimethyl-1H-pyrazol-5-yl)-N-((5- fluoro-2,3-dihydrobenzofuran-4- yl)methyl)imidazo[1,2-c]pyrimidin- 5-amine 33

¹H NMR (400 MHz, DMSO-d₆) δ ppm = 8.26 (br s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 6.93 (t, J = 9.2 Hz, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 6.19 (s, 1H), 4.71 (s, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.80 (br d, J = 6.0 Hz, 2H), 3.69 (s, 3H), 3.29-3.26 (m, 2H), 2.20-2.14 (m, 4H), 0.39-0.34 (m, 2H), 0.30-0.24 (m, 2H). LCMS [M + 1]: 448.3. 2-((cyclopropylamino)methyl)-8-(1,3- dimethyl-1H-pyrazol-5-yl)-N-((5- fluoro-2,3-dihydrobenzofuran-4- yl)methyl)imidazo[1,2-c]pyrimidin- 5-amine

Example 34

2-(1-aminoethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-5-amine

Step A: A mixture of tert-butyl (1-(8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (70.0 mg, 138 μmol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (81.9 mg, 276 μmol, 2.00 eq.), Pd(dppf)Cl₂ (10.1 mg, 13.8 μmol, 0.10 eq.) and sodium bicarbonate (34.8 mg, 415 μmol, 16.1 μL, 3.00 eq.) in a mixture solvent of water (0.40 mL) and dioxane (2.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100° C. for 30 minutes under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was evaporated to give a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to give tert-butyl (1-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (80.0 mg, crude) as yellow oil. LCMS [M+1]: 596.1.

Step B: A solution of tert-butyl (1-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (80.0 mg, 134 μmol, 1.00 eq.) in a mixture solvent of dichloromethane (3.00 mL) and trifluoroacetic acid (1.00 mL), the reaction mixture was stirred at 25° C. for 30 minutes. After completion of the reaction, the reaction mixture was evaporated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 22%-52%,10 min) to give 2-(1-aminoethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[1,2-c]pyrimidin-5-amine (25.9 mg, 50.0 μmol, 37.2% yield, 95.6% purity) as a white solid. LCMS [M+1]: 496.3.

¹H NMR (400M Hz, CD₃OD) δ=7.91 (s, 1H), 7.85 (dd, J=1.6, 8.0 Hz, 1H), 7.80 (s, 1H), 7.62 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 6.92-6.78 (m, 1H), 6.64 (dd, J=4.0, 8.8 Hz, 1H), 4.82 (s, 2H), 4.57 (t, J=8.8 Hz, 2H), 4.35-4.18 (m, 1H), 3.41-3.34 (m, 2H), 3.16 (s, 3H), 2.31 (s, 3H), 1.46 (d, J=6.8 Hz, 3H).

Following the teachings of the General Reaction Schemes, Example 34, and the intermediates disclosed herein, Examples 35-39 were prepared as shown in Table 4.

TABLE 4 Characterization of EXAMPLES 35-39 Example # Structure Analytical Data 35

¹H NMR (400 MHz, DMSO-d₆) δ = 8.45 (s, 1H), 8.22 (t, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 6.98- 6.89 (m, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 4.71 (d, J = 4.0 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.02-3.97 (m, 1H), 3.34- 3.31 (m, 2H), 3.03 (s, 6H), 2.27 (s, 3H), 1.79 (br s, 1H), 1.30 (d, J = 6.8 Hz, 3H). LCMS [M + 1]: 490.4. 5-(2-(1-aminoethyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4- yl)methyl)amino)imidazo[1,2- c]pyrimidin-8-yl)-N,N,4- trimethylpicolinamide 36

¹H NMR (400 MHz, DMSO-d₆) δ = 8.39 (br s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 4.71 (br s, 2H), 4.54 (t, J = 8.8 Hz, 2H), 4.05-4.00 (m, 1H), 3.88 (s, 3H), 3.30-3.28 (m, 2H), 1.95 (br s, 2H), 1.33 (d, J = 6.8 Hz, 3H). LCMS [M + 1]: 476.3. 2-(1-aminoethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(1- methyl-3-(trifluoromethyl)-1H- pyrazol-5-yl)imidazo[1,2-c]pyrimidin- 5-amine 37

¹H NMR (400 MHz, CD₃OD) δ = 7.69 (s, 1H), 7.44 (s, 1H), 7.18 (s, 1H), 7.18- 7.14 (m, 1H), 7.14-7.09 (m, 1H), 6.79- 6.69 (m, 1H), 6.54 (dd, J = 3.6, 8.4 Hz, 1H), 4.70 (s, 2H), 4.46 (t, J = 8.4 Hz, 2H), 4.06-4.01 (m, 1H), 3.42 (s, 2H), 3.25 (t, J = 8.8 Hz, 2H), 2.19 (s, 6H), 2.09 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H). LCMS [M + 1]: 475.0. 2-(1-aminoethyl)-8-(4- ((dimethylamino)methyl)-2- methylphenyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4- yl)methyl)imidazo[1,2- c]pyrimidin-5-amine 38

¹H NMR (400 MHz, CD₃OD) δ = 8.43 (d, J = 5.6 Hz, 1H), 8.11-8.05 (m, 1H), 7.94 (s, 1H), 7.88-7.84 (m, 1H), 7.83 (s, 1H), 6.84 (t, J = 9.2 Hz, 1H), 6.63 (dd, J = 4.0, 8.8 Hz, 1H), 4.83 (s, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.27-4.22 (m, 1H), 3.38-3.33 (m, 2H), 2.60 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). LCMS [M + 1]: 419.3. 2-(1-aminoethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(2- methylpyridin-4-yl)imidazo[1,2- c]pyrimidin-5-amine 39

¹H NMR (400 MHz, CDCl₃) δ = 8.54 (dd, J = 1.6, 4.8 Hz, 1H), 7.68 (dd, J = 2.0, 8.0 Hz, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 7.22-7.18 (m, 1H), 6.91-6.84 (m, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 5.20 (br t, J = 5.6 Hz, 1H), 4.83 (d, J = 5.6 Hz, 2H), 4.64 (t, J = 8.8 Hz, 2H), 4.28-4.22 (m, 1H), 3.43 (t, J = 8.8 Hz, 2H), 2.52 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H). LCMS [M + 1]: 419.3. 2-(1-aminoethyl)-N-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-8-(2- methylpyridin-3-yl)imidazo[1,2- c]pyrimidin-5-amine

Example 40 5-(2-(1-aminoethyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-8-yl)-1-methyl-1H-pyrazole-3-carbonitrile

Step A: A mixture of methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate (263 mg, 988 μmol, 2.00 eq.), tert-butyl (1-(8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (250 mg, 494 μmol, 1.00 eq.), bis(tri-tert-butylphosphine) palladium (O) (50.5 mg, 98.7 μmol, 0.20 eq.) and potassium carbonate (341 mg, 2.47 mmol, 5.00 eq.) in a mixture solvent of dioxane (5.00 mL) and water (1.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was evaporated to give a residue. The residue was purified by column chromatography (SiO₂, dichloromethane/methanol=1/0 to 10/1) to give methyl 5-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-8-yl)-1-methyl-1H-pyrazole-3-carboxylate (270 mg, 434 μmol, 88.0% yield, 91.0% purity) as an off-white solid. LCMS [M+1]: 566.6.

¹H NMR (400 MHz, CD₃OD) δ=7.81 (s, 1H), 7.78 (s, 1H), 6.95 (s, 1H), 6.85 (t, J=9.6 Hz, 1H), 6.64 (dd, J=4.0, 8.8 Hz, 1H), 4.83 (s, 2H), 4.58 (t, J=8.8 Hz, 2H), 4.15-4.10 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.41-3.35 (m, 2H), 1.44 (s, 12H), 1.41 (s, 3H).

Step B: A mixture of methyl 5-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-8-yl)-1-methyl-1H-pyrazole-3-carboxylate (250 mg, 402 μmol, 1.00 eq.) and sodium hydroxide (1.00 M in water, 1.21 mL, 3.00 eq.) in methanol (10.0 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 50° C. for 1 hour under a nitrogen atmosphere. After completion of the reaction, the mixture was acidified to pH=7 with hydrochloric acid aqueous solution (1.00 M). During this period, white precipitate was formed, the suspension was filtered, the filter cake was collected and dried in vacuo to give 5-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-8-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (250 mg, crude) as a white solid which was used directly.

1H NMR (400 MHz, DMSO-d₆) δ=8.41 (s, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 7.22 (br d, J=7.6 Hz, 1H), 6.96-6.87 (m, 1H), 6.69 (dd, J=4.0, 8.8 Hz, 1H), 6.50 (s, 1H), 4.77-4.66 (m, 3H), 4.54 (t, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.31-3.28 (m, 2H), 1.40 (s, 3H), 1.38 (s, 9H).

Step C: To a solution of 5-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-8-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (230 mg, 417 μmol, 1.00 eq.) and ammonium chloride (66.9 mg, 1.25 mmol, 3.00 eq.) in DMF (3.00 mL) was added diisopropylethylamine (162 mg, 1.25 mmol, 218 μL, 3.00 eq.) and HATU (238 mg, 625 μmol, 1.50 eq.). The mixture was stirred at 25° C. for 30 minutes. After completion of the reaction, the reaction mixture was triturated with water (20.0 mL), the suspension was filtered and the cake was collected and dried under reduced pressure to give the crude tert-butyl (1-(8-(3-carbamoyl-1-methyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (140 mg, 254 μmol, 61.0% yield) as a white solid which was used into the next step directly.

¹H NMR (400 MHz, DMSO-d₆) δ=8.42 (t, J=4.4, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 7.26-7.19 (m, 1H), 6.99-6.91 (m, 1H), 6.79 (s, 1H), 6.70 (dd, J=4.0, 8.8 Hz, 1H), 4.82-4.65 (m, 3H), 4.55 (t, J=8.8 Hz, 2H), 3.85 (s, 3H), 3.30-3.29 (m, 2H), 1.41 (s, 3H), 1.39 (s, 9H).

Step D: To a mixture of tert-butyl (1-(8-(3-carbamoyl-1-methyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (120 mg, 218 μmol, 1.00 eq.) and triethylamine (441 mg, 4.36 mmol, 607 μL, 20.0 eq.) in anhydrous tetrahydrofuran (2.00 mL) was added trifluoroacetic anhydride (458 mg, 2.18 mmol, 303 μL, 10.0 eq.) at 0° C., The resulting mixture was warmed to 25° C. and stirred for 30 minutes. The reaction mixture diluted with ammonium chloride aqueous solution (20.0 mL) and the suspension was filtered, and the filtrate was extracted with ethyl acetate (30.0 mL×2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl (1-(8-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (120 mg, crude) as a yellow oil which used directly. LCMS [M+1]: 533.3.

Step E: A solution of tert-butyl (1-(8-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)ethyl)carbamate (120 mg, 225 μmol, 1.00 eq.) in a mixture solvent of dichloromethane (1.50 mL) and trifluoroacetic acid (0.50 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was evaporated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 22%-52%,10 min) to give 5-(2-(1-aminoethyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-8-yl)-1-methyl-1H-pyrazole-3-carbonitrile (4.70 mg, 10.6 μmol, 4.72% yield, 97.8% purity) as a white solid. LCMS [M+1]: 433.3.

¹H NMR (400 MHz, CD₃OD) δ=7.82 (s, 1H), 7.79 (s, 1H), 6.95 (s, 1H), 6.87-6.80 (m, 1H), 6.63 (dd, J=4.0, 8.8 Hz, 1H), 4.82 (s, 2H), 4.56 (t, J=8.8 Hz, 2H), 4.18-4.13 (m, 1H), 3.87 (s, 3H), 3.37 (t, J=8.4 Hz, 2H), 1.49 (d, J=6.4 Hz, 3H).

Example 41

2-(amino(cyclopropyl)methyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine

Step A: To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (50.0 mg, 129 μmol, 1.00 eq.) in THF (1.00 mL) was added cyclopropyl magnesium bromide (0.50 M, 1.55 mL, 6.00 eq.) dropwise at 15° C., the mixture was stirred at 25° C. for 5 hours, then the reaction mixture was cooled to −10° C. Methanol (0.50 mL) was added to the reaction mixture, after 15 mins the reaction mixture was added sodium borohydride (19.5 mg, 515 μmol, 4.00 eq.) and stirred at 0° C. for 2 hours. Aqueous sodium bicarbonate (10.0 mL) was added to the reaction mixture and then extracted with ethyl acetate (10.0 mL×3), combined and dried over sodium sulfate, concentrated to give 2-(amino(cyclopropyl)methyl)-8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (50.0 mg, 95.0 μmol, 74.0% yield, 82.0% purity) as yellow oil which was used for the next step without further purification.

Step B: To a mixture of 2-(amino(cyclopropyl)methyl)-8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (61.0 mg, 116 μmol, 1.00 eq.) and TEA (35.1 mg, 347 μmol, 48.3 μL, 3.00 eq.) in THF (2.00 mL) was added di-tert-butyl dicarbonate (50.5 mg, 231 μmol, 53.1 μL, 2.00 eq.) and DMAP (1.41 mg, 11.6 μmol, 0.10 eq.) in one portion at 20° C. under a nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 3 hours. Water (3.00 mL) was added to the reaction mixture and then extracted with ethyl acetate (3.00 mL×2). The combined organic phase was washed with brine (8.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=1/1) to afford the final product tert-butyl ((8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(cyclopropyl)methyl)carbamate (40.0 mg, 75.1 μmol, 65.0% yield) as a yellow oil which used for the next step without further purification. LCMS [M+1]: 532.0.

Step C: tert-butyl ((8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)(cyclopropyl)methyl)carbamate (40.0 mg, 75.1 μmol, 1.00 eq.), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 mg, 90.2 μmol, 1.20 eq.), Pd(dppf)Cl₂ (5.50 mg, 7.51 μmol, 0.10 eq.) and sodium bicarbonate (18.9 mg, 225 μmol, 8.77 μL, 3.00 eq.) in dioxane (1.00 mL) and water (0.20 mL) was degassed and then heated to 100° C. for 2 hours under nitrogen atmosphere. The mixture was cooled to 20° C. and concentrated in reduced pressure. Water (10.0 mL) was added to the reaction mixture and then extracted with ethyl acetate (10.0 mL×3). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=1/1) to afford tert-butyl (cyclopropyl(8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methyl)carbamate (20.0 mg, 36.5 μmol, 48.6% yield) as a yellow oil which was used for the next step without further purification. LCMS [M+1]: 548.4.

Step D: To a mixture of tert-butyl (cyclopropyl(8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidin-2-yl)methyl)carbamate (20.0 mg, 36.5 μmol, 1.00 eq.) in DCM (0.50 mL) was added TFA (770 mg, 6.75 mmol, 0.50 mL, 185 eq.) in one portion at 20° C. under a nitrogen atmosphere. The mixture was stirred at 20° C. for 2 hours. The solvent was removed under reduce pressure to give a residue which purified by prep-HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 32%-62%,10 min) to give 2-(amino(cyclopropyl)methyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (10.0 mg, 22.3 μmol, 61.1% yield, 99.9% purity) as a white solid. LCMS [M+1]: 448.4.

¹H NMR (400 MHz, CD₃OD) δ=7.95 (s, 1H), 7.73 (s, 1H), 6.91-6.82 (m, 1H), 6.66 (dd, J=4.0, 8.8 Hz, 1H), 6.25 (s, 1H), 4.83 (s, 2H), 4.59 (t, J=8.8 Hz, 2H), 3.74 (s, 3H), 3.38 (t, J=8.8 Hz, 2H), 3.29 (br d, J=8.8 Hz, 1H), 2.30 (s, 3H), 1.28-1.17 (m, 1H), 0.67-0.62 (m, 2H), 0.50-0.32 (m, 2H).

Example 42

2-(1-amino-2,2,2-trifluoroethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine

Step A: To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (80.0 mg, 197 μmol, 1.00 eq.) and di-tert-butyl dicarbonate (47.3 mg, 217 μmol, 49.7 μL, 1.10 eq.) in THF (1.00 mL) was added DMAP (2.40 mg, 19.7 μmol, 0.10 eq.). The reaction mixture was stirred at 35° C. for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=2/1) to give tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-formylimidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (85.0 mg, 168 μmol, 85.3% yield) as a gray solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.08 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 6.82-6.76 (m, 1H), 6.61 (dd, J=4.0, 8.8 Hz, 1H), 6.51 (s, 1H), 5.07 (s, 2H), 4.52 (t, J=8.8 Hz, 2H), 3.76 (s, 3H), 3.28-3.29 (m, 2H), 2.22 (s, 3H), 1.32 (s, 9H).

Step B: To a solution of tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-formylimidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (85.0 mg, 168 μmol, 1.00 eq.) and potassium carbonate (46.4 mg, 336 μmol, 2.00 eq.) in DMF (1.00 mL) was added trimethyl(trifluoromethyl)silane (191 mg, 1.34 mmol, 8.00 eq.) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 12 hours. The reaction was poured into water (3.00 mL) and stirred for 15 mins. The aqueous phase was extracted with ethyl acetate (3.00 mL×2). The combined organic phases were washed with brine (3.00 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (85.0 mg, 147 μmol, 87.9% yield) as a gray solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.11 (s, 1H), 7.60 (s, 1H), 7.01 (d, J=6.8 Hz, 1H), 6.80-6.74 (m, 1H), 6.61 (dd, J=4.0, 8.8 Hz, 1H), 6.46 (s, 1H), 5.34 (t, J=6.8 Hz, 1H), 5.07 (s, 2H), 4.52 (t, J=8.8 Hz, 2H), 3.72 (s, 3H), 3.29-3.26 (m, 2H), 2.21 (s, 3H), 1.29 (s, 9H).

Step C: To a solution of tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (22.0 mg, 38.2 μmol, 1.00 eq.) in DCE (1.00 mL) was added manganese dioxide (6.60 mg, 76.3 μmol, 2.00 eq.). The mixture was stirred at 40° C. for 1 hour. The mixture was filtered and concentrated in vacuo to give tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(2,2,2-trifluoroacetyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (16.0 mg, crude) as a white solid which was used without further purification in the next step.

Step D: To a solution of tert-butyl (8-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(2,2,2-trifluoroacetyl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (12.0 mg, 20.9 μmol, 1.00 eq.) in THF (0.50 mL) was added ammonia (711 μg, 41.8 μmol, 2.00 eq.) and titanium isopropoxide (11.9 mg, 41.8 μmol, 12.3 μL, 2.00 eq.), the mixture was to adjust pH=4 with acetic acid (0.10 mL) and stirred at 40° C. for 30 minutes. Then the mixture was added sodium cyanoborohydride (2.63 mg, 41.8 μmol, 2.00 eq.) and stirred at 40° C. for another 2 hours. The mixture was poured into saturated ammonium chloride (3.00 mL) and stirred for 15 mins. The aqueous phase was extracted with dichloromethane (3.00 mL×5). The combined organic phases were washed with brine (3.00 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl (2-(1-amino-2,2,2-trifluoroethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (12.0 mg, crude) as a white solid. LCMS [M+1]: 576.5.

Step E: To a solution of tert-butyl (2-(1-amino-2,2,2-trifluoroethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)imidazo[1,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (10.0 mg, 17.4 μmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.30 mL). The mixture was stirred at 25° C. for 30 minutes. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25 mm x 5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 27%-57%, 10 min) to give 2-(1-amino-2,2,2-trifluoroethyl)-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,2-c]pyrimidin-5-amine (6.00 mg, 12.2 μmol, 70.0% yield, 96.4% purity) as a white solid. LCMS [M+1]: 476.4.

¹H NMR (400 MHz, DMSO-d₆) δ=8.42 (br s, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 6.98-6.89 (m, 1H), 6.70 (dd, J=4.0, 8.8 Hz, 1H), 6.20 (s, 1H), 4.71 (br s, 2H), 4.68-4.60 (m, 1H), 4.55 (t, J=8.8 Hz, 2H), 3.68 (s, 3H), 3.31-3.27 (m, 2H), 2.43 (br d, J=7.2 Hz, 2H), 2.18 (s, 3H).

Example 43

8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(2H-tetrazol-5-yl)imidazo[1,2-c]pyrimidin-5-amine

Step A: A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (250 mg, 644 μmol, 1.00 eq.), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (215 mg, 966 μmol, 1.50 eq.), Pd(dppf)Cl₂ (47.1 mg, 64.4 μmol, 0.10 eq.) and sodium bicarbonate (162 mg, 1.93 mmol, 75.1 μL, 3.00 eq.) in dioxane (1.70 mL) and water (0.30 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 95° C. for 1 hour under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled and filtered, the filtrate was concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=3/1 to 1/1) to give 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (170 mg, 379 μmol, 58.9% yield, 90% purity) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.92 (s, 1H), 8.63 (t, J=4.8 Hz, 1H), 7.86 (s, 1H), 7.02-6.90 (m, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.72 (d, J=4.8 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.67 (s, 3H), 3.32-3.30 (m, 2H), 2.18 (s, 3H).

Step B: To a mixture of -(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (20.0 mg, 44.6 μmol, 1.00 eq.) and ammonium chloride (2.50 mg, 46.7 μmol, 1.05 eq.) in DMF (1.00 mL) was added sodium azide (3.00 mg, 46.1 μmol, 1.03 eq.). The reaction mixture was heated at 100° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled and diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL×3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%) to afford 8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(2H-tetrazol-5-yl)imidazo[1,2-c]pyrimidin-5-amine (19.7 mg, 43.1 μmol, 96.6% yield, 97.7% purity) as a white solid. LCMS [M+1]: 447.1.

¹H NMR (400 MHz, DMSO-d₆) δ=8.99 (s, 1H), 8.64 (s, 1H), 7.80 (s, 1H), 7.04-6.87 (m, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 6.26 (s, 1H), 4.75 (d, J=4.8 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.71 (s, 3H), 3.37-3.31 (m, 2H), 2.20 (s, 3H).

Example 44

8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(1,3,4-oxadiazol-2-yl)imidazo[1,2-c]pyrimidin-5-amine

Step A: A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (800 mg, 1.84 mmol, 1.00 eq.), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (612 mg, 2.76 mmol, 1.50 eq.), NaHCO₃ (463 mg, 5.51 mmol, 214 μL, 3.00 eq.) and Pd(dppf)Cl₂ (134 mg, 184 μmol, 0.10 eq.) in water (1.60 mL) and dioxane (8.00 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 105° C. for 2 hours under a nitrogen atmosphere. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 0/1) to give ethyl 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (750 mg, 1.66 mmol, 90.6% yield) as a yellow solid. LCMS [M+1]: 451.0.

Step B: To a solution of ethyl 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (400 mg, 888 μmol, 1.00 eq.) in ethanol (4.00 mL) was added hydrazine hydrate (178 mg, 3.55 mmol, 173 μL, 4.00 eq.) at 25° C. The mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), filtered, the filter cake was collected and dried to give 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbohydrazide (190 mg, 435 μmol, 49.0% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.48 (br s, 1H), 8.65 (s, 1H), 8.48 (br s, 1H), 7.75 (s, 1H), 6.93 (br t, J=8.8 Hz, 1H), 6.74-6.65 (m, 1H), 6.27 (s, 1H), 4.71 (br d, J=3.6 Hz, 2H), 4.54 (br t, J=8.8 Hz, 2H), 4.48 (br s, 2H), 3.72 (s, 3H), 3.30-3.28 (m, 2H), 2.18 (s, 3H).

Step C: To a solution 8-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbohydrazide (50.0 mg, 97.4 μmol, 1.00 eq.) in triethoxymethane (2.00 mL) and DMSO (2.00 mL) was added ammonium chloride (20.8 mg, 390 μmol, 4.00 eq.), the reaction mixture was stirred at 130° C. for 1 hour. The reaction was concentrated in vacuo to give a residue, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5 μM; mobile phase: [phase A: water (10 mM NH₄HCO₃), phase B: ACN]) and lyophilization to give 8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(1,3,4-oxadiazol-2-yl)imidazo[1,2-c]pyrimidin-5-amine (10.3 mg, 21.1 μmol, 21.7% yield, 91.4% purity) as a white solid. LCMS [M+1]: 447.3.

¹H NMR (400 MHz, DMSO-d₆) δ=9.34 (s, 1H), 8.91 (br s, 1H), 8.62 (br s, 1H), 7.79 (s, 1H), 6.95 (br t, J=9.2 Hz, 1H), 6.70 (br dd, J=3.6, 8.4 Hz, 1H), 6.24 (s, 1H), 4.73 (s, 2H), 4.55 (br t, J=8.4 Hz, 2H), 3.72 (s, 3H), 3.37-3.34 (m, 2H), 2.20 (s, 3H).

Example 45

8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(oxazol-5-yl)imidazo[1,2-c]pyrimidin-5-amine

To a solution of 8-(1,3-dimethyl-1H-pyrazol-5-yl)-54(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbaldehyde (80.0 mg, 196 μmol, 1.00 eq.) in methanol (2.00 mL) were added p-toluenesulfonylmethyl isocyanide (64.0 mg, 328 μmol, 1.67 eq.) and potassium carbonate (81.6 mg, 590 μmol, 3.00 eq.). The reaction was stirred at 65° C. for 2 hours. The suspension was filtered, the cake was collected and triturated with methanol (5.00 mL), then dried under vacuum to give 8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-(oxazol-5-yl)imidazo[1,2-c]pyrimidin-5-amine (37.4 mg, 80.2 μmol, 40.7% yield, 95.5% purity) as a white solid. LCMS [M+1]: 446.2.

¹H NMR (400 MHz, CD₃OD) δ=8.31 (s, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 6.85 (t, J=9.2 Hz, 1H), 6.64 (dd, J=3.6, 8.8 Hz, 1H), 6.26 (s, 1H), 4.83-4.80 (m, 2H), 4.57 (t, J=8.8 Hz, 2H), 3.74 (s, 3H), 3.38 (t, J=8.8 Hz, 2H), 2.29 (s, 3H).

The compounds of the present invention may have one or more chiral center and, if so, are synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer's instructions, as well as methods described herein, e.g., EXAMPLES 11 and 12. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention.

Also contemplated within the scope of the invention are variants of compounds of the present invention in which one or more hydrogen atoms have been replaced with deuterium. As exemplified herein, Intermediates B-7, B-8, C-7, C-8 and D-31 have one or more hydrogen atom replaced with deuterium. By substituting one or more hydrogen for deuterium on the Intermediates A D exemplified herein, deuterated versions of the compounds of the present invention can be readily generated using methods well known in the art.

Example A

This Example illustrates that exemplary compounds of the present invention inhibit PRC2 enzymatic activity.

Ten-point dose-response curves for compounds of the present invention were determined using a Hot Spot HMT assay (Reaction Biology Corp; see Horiuchi et al., Assay Drug Dev Technol. (2013) 4: 227-236 doi: 10.1089/adt.2012.480). The assay uses purified human, His-tagged PRC2 complex, including N-terminal His-tagged EZH2 enzyme, N-terminal Flag-tagged embryonic ectoderm development protein (EED), N-terminal His-tagged suppressor of zeste 12 (SUZ12), N-terminal His-tagged AEBP2, and N-terminal His-tagged RbAp48. In this assay, the transfer of the tritiated methyl group from radiolabeled S-adenosyl methionine (SAM) to purified core histone protein by EZH2 is quantitated after filtration to determine the activity of the core PRC2 complex in the presence and absence of compound.

Briefly, compounds of the present invention were solubilized in DMSO and a series of 10, three-fold serial dilutions were made for each compound in 15% DMSO. The initial starting concentration for the serial dilutions of each compound was 1.0 μM. Control samples lacking compound, EZH2 enzyme or various reaction components also were prepared and processed in parallel with compound test samples. SAH (S-(5-adenosyl)-L-homocysteine) was used as a positive control for assay validation.

An aliquot of each serial dilution of test compound was added to deep 384 well plate using Acoustic Technology instrument (Echo 550, LabCyte) containing reaction buffer (50 mM Tris-HCl (pH 8.)), 0.01% Brij35, 1 mM EDTA, 1 mM DTT, 1 mM PMSF and 1% DMSO), 10 nM purified PRC2 complex and 0.05 mg/ml core histone H3 in a 5 μl volume. The reaction was mixed gently and then pre-incubated for 20 min at 30° C. The enzymatic reaction was initiated by adding 1 uM S-Adenosyl-L-[methyl ³H]methionine and incubated for 1 hr at 30° C. After 1 hr, the reaction product was detected using a filter binding method and the amount of tritiated H3 core histone was quantitated using a scintillation counter. The IC₅₀ value for each compound was determined from each 10-point dose-response curve using GraphPad Prism software and the results for exemplary compounds of Formula (I) are shown in Table 5. Key: A=≤250 nM; B=>250 nM—≤500 nM; and C=>500 nM—≤2 μM.

TABLE 5 Inhibition of PRC2-mediated Enzymatic Activity by Exemplary Compounds of Formula (I) Example No. IC₅₀ 1 A 2 A 3 C 4 C 5 C 6 B 7 A 8 B 9 C 10 A 11 C 12 A 13 A 14 B 15 B 16 C 17 C 18 A 19 A 20 A 21 C 22 C 23 C 24 C 25 B 26 C 27 C 28 C 29 C 30 C 31 C 32 C 33 C 34 A 35 A 36 A 37 A 38 A 39 A 40 A 41 A 42 B 43 A 44 A 45 A

Example B

This Example illustrates that exemplary compounds of the present invention inhibit the growth of tumor cells harboring PRC2 complexes containing EZH2 activating mutations.

The Pfeiffer cell line was established from a pleural infusion from a patient having metastatic diffuse large B-cell lymphoma (DLBCL). This cell line expresses a mutant form of the EZH2 enzyme (A677G) that results in enhanced EZH2 activity leading to increased methylation of histone H3 Lys27. Increased trimethylation of histone H3 Lys27 is believed to be implicated in tumorgenesis and poor clinical prognosis in lymphomas (McCabe et al., (2012) Nature 492:108-112).

Inhibition of PRC2-mediated histone H3 methylation by compounds of Formula (I) was measured by ELISA using a Tri-Methyl Histone H3 (Lys 27) Sandwich ELISA Kit (Cell Signaling Tech #7866C) in accordance with the manufacturer's instructions. Briefly, Pfeiffer cells were cultured in RPMI medium supplemented with 10% fetal bovine serum and 1% penicillin and 1% streptomycin in 96 well culture plates at 37° C. to a density of 8000 cells/90 μl/well and the cells were harvested. A series of 3-fold serial dilutions of each test compound of Formula (I) were prepared in RPMI medium and added to the cells at final concentrations ranging from 1 μM to 0.15 nM. The plates were incubated at 37° C. for 96 hours.

After incubation, the cells were pelleted by centrifugation in a pre-cooled 4° C. rotor at 1,100 rpm for 10 min and the supernatant was removed by aspiration. The cell pellet was resuspended in 55 μl of Lysis Buffer (0.4M HCl) and incubated on ice with periodic shaking for 30 minutes. The lysed cells were subjected to centrifugation at 4,200 rpm for 10 min at 4° C. and the supernatant containing acid-soluble proteins was collected and the remainder discarded. The acid-soluble proteins were brought to a neutral pH by the addition of 20 μl of Neutralization Buffer (1 M Sodium phosphate, dibasic (pH 12.5), 2.5 mM DTT and 1 mM PMSF) and the neutralized lysates were analyzed by ELISA.

A 65 μl aliquot of each cell lysate was added to a well of a microwell strip, the microwells were sealed using tape and incubated either at 37° C. for two hours or at 4° C. overnight. After incubation, the tape was removed at the microwells were washed four times using 200 μl of 1× Wash Buffer. To each washed microwell, a 100 μl aliquot of an anti-trimethyl histone H3 Lys27 Detection Antibody solution was added and the microwells were incubated at 37° C. for one hour. The Detection Antibody solution was removed by aspiration and the wells were washed four times each using 200 μl of 1× Wash Buffer.

A 100 μl aliquot of an HRP-linked secondary antibody was added to each well, the wells were sealed with tape and incubated at 37° C. for 30 min. The HRP-linked secondary antibody solution was removed by aspiration and the wells were washed four times using 200 μl of 1× Wash Buffer. A 100 μl aliquot of a TMB substrate was added to each well, the wells were sealed with tape and incubated at 37° C. for 10 min or 25° C. for 30 min. The reaction was stopped by the addition of 100 μl aliquot of a STOP solution and the plate was shaken briefly. The degree of histone H3 trimethylation was determined using a spectrophotometric readout by measuring the absorbance at 450 nm and then calculating the amount of trimethylated histone H3. The results are shown in Table 6. Key: A=≤250 nM; B=>250 nM-≤500 nM; and C=>500 nM-≤5 μM.

TABLE 6 Inhibition of EZH2-mediated Histone H3 Trimethylation by Exemplary Compounds of Formula (I) Example No. IC₅₀ 6 A 7 A 9 C 10 A 11 A 12 A 13 A 15 A 16 C 17 C 18 A 19 B 20 B 21 C 22 C 23 C 24 B 27 C 28 C 29 C 30 B 31 C 32 B 33 B 34 A 35 A 36 A 37 A 38 A 39 A 40 A 41 A 44 A 45 B

Example C

This Example illustrates that exemplary compounds of the present invention exhibit a greater potency against DLBCL cell lines expressing an activating mutant form of EZH2 enzyme than wild type EZH2.

Karpas 422 cell line is a human B cell non-Hodgkin's lymphoma cell line established from a female patient having DLBCL. This EZH2 heterozygotic cell line expresses a mutant form of EZH2 enzyme (Y641N) that increases histone H3 methylation and this mutation has been implicated in the tumorgenesis of lymphomas, such as DLBCL.

Karpas 422 cells (PHE cat no., 06101702) were cultured in RPMI medium supplemented with 20% fetal bovine serum and 1% penicillin/1% streptomycin and plated at a density of 1000 cells/90 μl/well in 96 well white assay plates. A dose response curve for compounds of the present invention was determined by adding a 10 μl aliquot of stock solutions of varying concentrations of compounds to the same medium in each well, over a concentration range of 10 μM using 3-fold dilutions to a final concentration of 1.5 nM. The plates were incubated at 37° C. for predetermined time periods, Day 4, Day 7, or Day 11, and the viability of the cells was measured using a CTG assay kit (Cell Titre Glo; Promega cat. no G7573) on Day 4 and Day 7 in accordance with the manufacturer's instructions.

For the viability assay for the Day 11 plates, the plates were subjected to centrifugation at 1100 rpm for five minutes on Day 7 and the supernatant was removed by aspiration. The cells were resuspended in 90 μl aliquot of the appropriate growth medium lacking the compound followed by addition of 10 μl of a 10× stock of the same compound at the same concentration. The viability of the Day 11 cells was measured using the CTG assay kit described above in accordance with the manufacturer's instructions. The IC₅₀ values for each compound at each predetermined time point were calculated using Graph pad PRISM software and the results are shown in Table 7. Key: A=≤250 nM; B=>250 nM-≤500 nM; C=>500 nM-≤5 μM and N.D.=not determined.

TABLE 7 Enhanced Potency of Exemplary Compounds Inhibiting Proliferation of Cells Expressing an Activating Mutant Form of EZH2 Example No. IC₅₀ 1 A 2 C 3 C 4 C 5 B 6 N.D. 7 C 8 N.D. 9 B 10 A 11 A 12 A 13 A 14 C 15 A 16 C 17 C 18 A 19 A 20 A 21 C 22 C 23 C 24 B 25 B 26 N.D. 27 C 28 C 29 C 30 A 31 C 32 A 33 B 34 A 35 A 36 A 37 A 38 A 39 A 40 A 41 A 42 N.D. 43 N.D. 44 A 45 A

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims. 

We claim:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single or a double bond; Z is O or S; X is O, CR¹⁰, CR¹¹OH, or C(R¹¹)₂, wherein: when X is O,

is a single bond; when X is C(R¹¹)₂,

is a single bond; when X is CR¹¹OH,

is a single bond; or when X is CR¹¹,

is a double bond; R¹ is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R⁴; R² is —C(R^(5a)R^(5b))R⁷ or heteroaryl; each R³ is independently C1-C3 alkyl or halogen; each R⁴ is independently cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, —Y²-haloalkyl; —Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, —Y¹-heterocyclyl, -L-N(R¹¹)₂, —Y¹—N(R¹¹)₂ or —Y²—N(R¹¹)₂ wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl or —Y¹— heterocyclyl is optionally substituted with one or more R⁹; L is a bond or C1-C4 alkylene; Y¹ is a bond, —C(O)—, or —NHC(O)—; Y² is a bond, —S—, —SO—, —SO₂—, or —NR¹⁰SO₂—, R^(5a) and R^(5b) are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R^(5a) or R^(5b) is hydrogen; R⁶ is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; R⁷ is —NR^(8a8b) wherein R^(8a) and R^(8b) together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from —O—, —N—, or —S— and optionally substituted with one or more R¹⁰; or R⁷ is —OR^(8a) or NHR^(8a) wherein R^(8a) is hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl; each R⁹ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R¹¹)₂, C1-C6 alkyl or —Y¹-heterocyclyl, wherein the —Y¹-heterocyclyl is optionally substituted with one or more R¹⁰; each R¹⁰ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl; each R¹¹ is independently hydrogen or C1-C3 alkyl; and n is 1 or
 2. 2. The compound of claim 1, wherein Z is O.
 3. The compound of claim 1, wherein Z is S.
 4. The compound according to any of claim 2 or 3, wherein n is
 1. 5. The compound according to any of claims 2-4, wherein X is C(R¹¹)₂ and

is a single bond.
 6. The compound according to any of claims 2-4, wherein X is CR¹¹ and

is a double bond.
 7. The compound according to any of claims 2-4, wherein X is O and

is a single bond.
 8. The compound according to any of claims 2-7 wherein R¹ is aryl optionally substituted with one or more R⁴.
 9. The compound of claim 8, wherein the aryl is phenyl optionally substituted with one or more R⁴.
 10. The compound of claim 9, wherein the phenyl is substituted with one, two or three R⁴.
 11. The compound of claim 10, wherein the one, two or three R⁴ are each independently halogen, hydroxyl, haloalkyl, —COOR¹¹, —Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, -L-N(R¹¹)₂, —O-L-N(R¹¹)₂, —C(CF₃)N(R¹¹)₂, —Y¹—N(R¹¹)₂, —Y²—N(R¹¹)₂, —Y²-haloalkyl, -L-heterocyclyl, or —Y¹-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl and —Y¹-heterocyclyl is optionally substituted with one or more R⁹.
 12. The compound of claim 11, wherein R⁴ is —Y¹—C1-C6 alkyl and Y¹ is a bond and the C1-C6 alkyl is methyl, ethyl, isopropyl, butyl or pentyl.
 13. The compound of claim 11, wherein R⁴ is —Y²—C1-C6 alkyl and Y² is a —SO₂— and the C1-C6 alkyl is methyl.
 14. The compound of claim 11, wherein R⁴ is —Y²-haloalkyl and Y² is —S— or —SO₂— and the haloalkyl is trifluoromethyl.
 15. The compound of claim 11, wherein R⁴ is -L-N(R¹¹)₂ and L is a bond and each R¹¹ is hydrogen, each R¹¹ is methyl or one R¹¹ is methyl and one R¹¹ is hydrogen.
 16. The compound of claim 11, wherein R⁴ is -L-N(R¹¹)₂ and L is methylene or ethylene and each R¹¹ is hydrogen, each R¹¹ is methyl or one R¹¹ is methyl and one R¹¹ is hydrogen.
 17. The compound of claim 11, wherein R⁴ is —Y¹—N(R¹¹)₂, Y is —C(O)— and each R¹¹ independently is hydrogen, each R¹¹ is independently methyl or one R¹¹ is methyl and one R¹¹ is hydrogen.
 18. The compound of claim 11, wherein R⁴ is —Y²—N(R¹¹)₂, Y² is —SO₂— and each R¹¹ independently is hydrogen, each R¹¹ is methyl or one R¹¹ is methyl and one R¹¹ is independently hydrogen.
 19. The compound of claim 11, wherein R⁴ is —Y¹-heterocyclyl and Y¹ is —C(O)— and the heterocyclyl portion of the -L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.
 20. The compound of claim 11, wherein R⁴ is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the -L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperdinyl, piperazinyl, or 3λ²-azabicyclo[3.1.0]hexanyl, each optionally substituted with one or more R⁹ selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl and/or halogen.
 21. The compound of claim 11, wherein R⁴ is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the -L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl or piperdinyl, each optionally substituted with one or more R⁹ selected from C1-C3 alkyl, alkoxy, hydroxyl and/or halogen.
 22. The compound of claim 11, wherein R⁴ is —Y¹-heterocyclyl and Y¹ is —C(O)— and the heterocyclyl portion of the —Y¹-heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
 23. The compound of claim 11, wherein R⁴ is -L-heteroaryl optionally substituted with one or more R⁹.
 24. The compound of claim 23, wherein the -L-heteroaryl is tetrazolyl.
 25. The compound of claim 11, wherein R⁴ is —PO₃(C1-C3 alkyl)₂.
 26. The compound of claim 11, wherein R⁴ is —COOR¹¹.
 27. The compound of claim 11, wherein R⁴ is hydroxyalkyl.
 28. The compound of claim 11, wherein R⁴ is —O-L-N(R¹¹)₂.
 29. The compound of claim 11, wherein R⁴ is aralkyl.
 30. The compound according to any of claims 2-7, wherein R¹ is heteroaryl optionally substituted with one or more R⁴.
 31. The compound of claim 30, wherein the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, each optionally substituted with one or more R⁴.
 32. The compound of claim 31, wherein the heteroaryl is substituted with one or more R⁴; wherein each R⁴ is independently cyano, halogen, —Y¹—C1-C6 alkyl, —Y²—C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R¹¹)₂, —Y¹—N(R¹¹)₂, -L-heteroaryl, -L-heterocyclyl, or —Y¹-heterocyclyl, wherein the heteroaryl of the -L-heteroaryl and the heterocyclyl portion of the -L-heterocyclyl and —Y¹— heterocyclyl are optionally substituted with one or more R⁹.
 33. The compound of claim 31, wherein the heteroaryl is pyrazolyl optionally substituted with one R⁴ independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, —Y¹—C1-C6 alkyl, -L-N(R¹¹)₂, -L-heterocyclyl or -L-heteroaryl, wherein the heteroaryl of the -L-heteroaryl and the heterocyclyl portion of the -L-heterocyclyl are optionally substituted with one or more R⁹.
 34. The compound of claim 33, wherein R⁴ is -L-heteroaryl and L is methylene where the heteroaryl is pyridyl optional substituted with one or more R⁹.
 35. The compound of claim 33, wherein R⁴ is -L-heterocyclyl optionally substituted with one or more R⁹ where L is a bond and the heterocyclyl portion of the -L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl.
 36. The compound of claim 33, wherein R⁴ is -L-heterocyclyl optionally substituted with one or more R⁹ where L is methylene and the heterocyclyl portion of the -L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl.
 37. The compound of claim 33, wherein R⁴ is -L-N(R¹¹)₂ where L is methylene and each R¹¹ is independently hydrogen, each R¹¹ is independently C1-C3 alkyl or one R¹¹ is C1-C3 alkyl and one R¹¹ is hydrogen.
 38. The compound of claim 33, wherein R⁴ is —Y¹—C1-C6 alkyl where Y¹ is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl.
 39. The compound of claim 33, wherein the heteroaryl is pyrazolyl optionally substituted with two R⁴ groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and —Y¹—C1-C6 alkyl.
 40. The compound of claim 33, wherein the heteroaryl is pyridyl optionally substituted with one R⁴ independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, —Y¹—C1-C6 alkyl, -L-N(R¹¹)₂, —Y¹—N(R¹¹)₂, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or more R⁹.
 41. The compound according to any of claims 2-7 wherein R¹ is -L-cycloalkyl optionally substituted with one or more R⁴.
 42. The compound according to any of claims 2-7 wherein R¹ is -L-heterocyclyl optionally substituted with one or more R⁴.
 43. The compound of claim 42, wherein L is a bond and the heterocyclyl is piperdinyl or tetrahydropyranyl.
 44. The compound according to any of claim 2 or 3, wherein n is two.
 45. The compound according to any of claims 2-44, wherein R² is —C(R^(5a)R^(5b))R⁷.
 46. The compound of claim 45, wherein R^(5a) is hydrogen and R^(5b) is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl.
 47. The compound of claim 45, wherein R^(5a) is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl and R^(5b) is hydrogen.
 48. The compound according to any of claim 45 or 46, wherein R⁷ is —OR^(8a).
 49. The compound of claim 48, wherein R^(8a) is hydrogen or C1-C3 alkyl.
 50. The compound according to any of claim 45 or 46, wherein R⁷ is —NR^(8a)R^(8b).
 51. The compound of claim 50, wherein R^(8a) and R^(8b) are each hydrogen.
 52. The compound of claim 50, wherein R^(8a) is hydrogen and R^(8b) is C1-C3 alkyl, halosulfonylalkyl, cycloalkyl or aralkyl.
 53. The compound according to any of claim 45 or 46, wherein R⁷ is —NR^(8a)R^(8b) wherein R^(8a) and R^(8b) together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from —O—, —N—, or —S— and optionally substituted with one or more R¹⁰.
 54. The compound of claim 53, wherein the 4-8 membered saturated or partially saturated heterocyclyl is azetidinyl or 3-hydroxy-azetidinyl.
 55. The compound according to any of claims 2-44, wherein R² is heteroaryl.
 56. The compound of claim 55, wherein the heteroaryl is tetrazolyl, oxazolyl or oxidiazolyl.
 57. The compound of claim 1, wherein the compound is:


58. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula I according to any one of claims 1-57 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
 59. A method for inhibiting PRC2 activity in a cell, comprising contacting the cell in which inhibition of PRC2 activity is desired with an effective amount of a compound of formula I according to any one of claims 1-57 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim
 58. 60. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of formula I according to any one of claims 1-57 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.
 61. The method of claim 60, wherein the therapeutically effective amount of the compound is between about 0.01 to 300 mg/kg per day.
 62. The method of claim 61, wherein the therapeutically effective amount of the compound is between about 0.1 to 100 mg/kg per day.
 63. The method according to any one of claims 60-62, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
 64. The method according to any one of claims 60-63, wherein the cancer is a PRC2-associated cancer.
 65. The method of claim 64, wherein the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer. 